Clin. Pharmacokinet. 22 (4): 254-273, 1992 0312-5963/ 92/0004-0254/ $10.00/ 0 © Adis International Limited. All rights reserved. CPKl
Clinical Pharmacokinetics in Veterinary Medicine J. Desmond Baggot Irish Equine Centre, Johnstown, County Kildare, Ireland, and School of Veterinary Medicine, University of California, Davis, California, USA
Contents 254 255 255 256 257 257 259 261 261
262 263 265 266 268 268 269 269 271
Summary I. Basis of Species Variations 1. 1 Species Differences in Dosage 1.2 Pharmacokinetic-Pharmacodynamic Relationships 1.3 Pharmacokinetic Applications 2. Pharmacokinetic Parameters 2.1 Species Variations in Drug Elimination 2.2 Extrapolation from Animals to Humans 3. Routes of Administration 3.1 Parenteral Administration 3.2 Oral Administration 3.3 Prolonged Release Products 4. Changes in Drug Disposition 5. The Neonatal Period 5. 1 Absorption 5.2 Distribution 5.3 Metabolism 5.4 Renal Excretion
Veterinary and human pharmacology differ principally in the range of species in which drugs are used and studied. In animals, as in humans, an understanding of the dose-effect relationship can be obtained by linking pharmacokinetic behaviour with pharmacodynamic information. Studies of different classes of drugs support the assumption that the range of therapeutic plasma concentrations in animals is generally the same as in humans. The requirement for species differences in dosage or administration rate (dose/dosage interval) may be attributed to variations in pharmacokinetic behaviour or pharmacodynamic activity, or both. When administering a drug orally, the bioavailability from a dosage form can vary widely. This is particularly the case between ruminant animals (cattle, sheep and goats), horses and carnivorous species (dogs and cats). Species variations in bioavailability can be avoided by parenteral administration. Formulation of parenteral preparations and location of intramuscular injection site can, at least in horses and cattle, influence bioavailability. Comparative pharmacokinetic studies help to explain differences in absorption and disposition processes that may underlie species variations in response to fixed dosages of a drug. Certain marker substances are useful in quantifying the activity of metabolic pathways or efficiency of excretion processes. Prediction of preslaughter withdrawal times in food-producing animals rep-
resents an application of pharmacokinetics in the field of drug residues. The drug residue profile can be obtained by combining fixed dose pharmacokinetic studies with measurement of drug concentrations in selected tissues and organs of the body. This approach offers an economical advantage in that fewer animals are required for residue studies. In domestic animals, as in humans, the disposition of most drugs can be interpreted in terms of a 2- (generally) or 3-compartment open model. Species variations in pharmacokinetic behaviour of a drug are usually attributed to differences in the rate of elimination rather than distribution and metabolism of the drug, although the principal metabolic pathway may differ. With certain notable exceptions, the herbivorous species (horses and ruminant animals) metabolise lipid-soluble drugs more rapidly than carnivorous species (dogs and cats). Humans metabolise drugs slowly in comparison with animals. Half-life values reflect this; insufficient data are available to base interspecies comparison on mean residence time. Intrinsic hepatic clearance of phenazone (antipyrine) [microsomal oxidation] in humans is approximately one-seventh of that in domestic animals. The physiological basis of species variations in the t'l2 values of drugs eliminated by a combination of biotransformation and excretion processes could be ascribed to differences in the rates of metabolic pathways and the influence of urinary pH on the extent of renal tubular reabsorption of unchanged drug. In any species, urinary pH is dependent mainly on dietary habit. For drugs eliminated entirely by renal excretion, allometric scaling of data obtained in animals can be used to predict pharmacokinetic parameters describing disposition in humans. Certain physiological states, prolonged (>48h) fasting, some disease conditions or pharmacokinetic drug interactions may alter the disposition of drugs in animals. The age-related development of hepatic microsomal associated drug metabolic pathways and renal excretion mechanisms also varies among species. In calves, lambs, kids, piglets and puppies these metabolic pathways develop rapidly during the first 3 to 4 weeks after birth. At 8 to 12 weeks they approach activity similar to that in adult animals. Renal function appears to mature within the first I to 2 weeks after birth in foals, calves, lambs, kids and piglets, while it takes longer (4 to 6 weeks) to mature in puppies. The rate of development of the major drug elimination processes in newborn animals is species-dependent.
The range of species in which drugs are used and studied distinguishes veterinary from human pharmacology. The mechanism of action of a drug is often the same in humans and other mammalian species. However, the intensity and duration of its effects can vary widely. This implies that species variations in the response produced by a fixed dosage of a drug can be attributed to differences in pharmacokinetic processes, pharmacodynamic sensitivity of tissue receptor sites or in the compensatory responses evoked. The dosage appropriate for the species can offset differences in the intensity of response to drugs. Thus, it is generally assumed that the range of therapeutic plasma concentrations in animals is the same as in humans. Studies of drugs of many pharmacological classes (e.g. pentobarbital, phenytoin, digoxin, theophylline) support this assumption.
When the interspecies comparison of pharmacokinetic parameters includes other orders of animals (e.g. birds, fish, reptiles), variation may be extreme. This can occur even when the principal elimination mechanism for the drug is renal excretion. For example, the average half-life (t'/2) of amikacin in gopher snakes is about 72h (Mader et al. 1985) compared with 1.0, 1.3, 1.7 and 2.3h in dogs, cats, horses and humans, respectively (Prescott & Baggot 1988). In African gray parrots the t,;, of amikacin is approximately Ih (Gronwall et al. 1989). 1.1 Species Differences in Dosage Differences in dosage across species may be attributed to variations in pharmacokinetic behaviour or in pharmacodynamic activity, or both. After oral administration, the bioavailability (i.e. the rate and extent of absorption) of the drug from a par-
Clin. Pharmacokinet. 22 (4) 1992
Table I. Some examples of species variations in drug dosage (adapted from Baggot 1989) Drug (route)
Morphine sulfate (1M)
Dog Cat Dog Horse Cattle Dog Cat Horse Cattle Dog Cat
1.0 0.1 2.0 1.1 0.2 0.3 1.0 0.1 0.02 10 q12h 10 q48h
Xylazine hydrochloride (1M)
Succinylcholine chloride (IV)
Abbreviations: 1M = intramuscular; IV qxh = every x hours.
= intravenous; PO = oral;
ticular dosage form can vary widely. This is particularly common between ruminant animals (i.e. cattle, sheep and goats), horses and the carnivorous species (dogs and cats). Variations in bioavailability can often be avoided by administering the dose parenterally. Low dosage requirements (relative to dogs) of morphine for cats and xylazine (an t¥2-adrenoceptor agonist) for cattle (table I) may be due to higher sensitivity of receptor sites in the central nervous system (pharmacodynamic variation) of these species for these drugs. Premedication with a phenothiazine tranquilliser can prevent the excitement induced by morphine in cats, an effect that might be attributed to blockade of central dopamine receptors. Similarly, in horses, acepromazine premedication will offset the increase in locomotor activity and excitement that morphine may produce when administered at the dosage required to produce visceral analgesia (Muir 1987). The effect of butorphanol, an opioid agonist-antagonist, on intestinal motility is less intense and induction of excitement is less likely, particularly when the drug is used with xylazine. Thus, butorphanol is preferred to morphine for the relief of moderate to severe abdominal pain (colic) in horses. The unusual sensitivity (manifested by neurological signs) of a subpopulation of Collies to oral ivermectin
100 ~g/kg is not associated with increased bioavailability or decreased clearance (CL) of the drug. Still, it could be due to variation in permeability of the blood-brain barrier and/or in the release of 'Y-aminobutyric acid in the CNS (Tranquilli et al. 1989). The wide variation among species in sensitivity to the neuromuscular blocking effect of succinylcholine is attributed to differences in activity of plasma pseudocholinesterase (Palmer et al. 1963; Stowe et al. 1958). This variation could be considered to have a pharmacokinetic rather than pharmacodynamic basis, since it is the rate of metabolism of the drug that accounts for the species differences. Most species differences in pharmacological effects after a fixed dosage of a drug are due to variations in pharmacokinetics, principally the rate of hepatic microsomal metabolism (oxidative reactions and glucuronide synthesis). These differences can generally be accommodated by adjusting the dosage interval. For example, the interval between aspirin doses in cats is 48h, which allows for their relative deficiency in glucuronyl transferase activity, compared with 12h in dogs (Davis 1979). Thiobarbiturates (thiopental and thiamylal) produce longer periods of struggling and relapses into sleep during recovery from anaesthesia in Greyhounds than in mixed-breed dogs (Robinson et al. 1986). This clinical observation correlates with higher plasma thiobarbiturate concentrations (Sams et al. 1985), which may be attributed to lower binding to plasma proteins in Greyhounds. In laboratory animals, drug elimination is generally more rapid than in domestic animals and humans due to the higher rate of basal metabolism in the various species of lab animals. Basal metabolism of warm-blooded animals depends on body surface area rather than bodyweight. Thus, small animal (laboratory) species require higher doses of drugs and shorter dosage intervals than larger species (van Miert 1989). 1.2 Pharmacokinetic-Pharmacodynamic Relationships The relationship between the dose of a drug and the clinically observed pharmacological effect may be complex. An understanding of the dose-effect
relationship is generally obtained by linking pharmacokinetic behaviour with information on pharmacodynamic activity (Holford & Sheiner 1981). Pharmacokinetic and pharmacodynamic models share drug concentration as a common feature. Pharmacokinetics defines the mathematical relationship that exists between the dose of a drug and the plasma concentration-time profile of the drug. Pharmacodynamics extends this relationship to the correlation between plasma drug concentrations and the pharmacological effect. The intensity of the pharmacological effect generally determines whether the desired clinical effect or a toxic effect will result. This assumes that measurable drug concentrations in the systemic circulation relate to the concentrations at the site of action. Studies of plasma concentration-effect relationships may provide information on the contribution of species variations in receptor sensitivity to observed differences in pharmacological response. Although the plasma concentration-effect relationship has been described for certain drug classes (e.g. antiarrhythmics, histamine H2-receptor antagonists, cardiac glycosides, neuromuscular blocking drugs), pharmacodynamic modelling is empirical. To gain a more complete understanding of the dose-plasma concentration-effect relationship, the use of combined pharmacokinetic-pharmacodynamic models that incorporate an effect compartment may be necessary. These are composed of a classical compartmental pharmacokinetic model, an effector compartment and an appropriate effect equation (Langmuir form) [fig. 1]. This modelling approach allows for the temporal relationship between plasma concentration and effect through a hypothetical 'effector' compartment (Colburn 1981, 1987, 1988). 1.3 Pharmacokinetic Applications The utility of pharmacokinetics in clinical pharmacology rests largely on the premise that the therapeutic range of plasma concentrations can be defined for a drug (Baggot 1977, 1983). The completeness of the plasma concentration-time curve depends on the sample collection times, the frequency and duration of sampling, and on the sen-
sitivity of the analytical procedure used to measure concentrations of the drug in plasma. Comparative pharmacokinetic studies provide a technique to clarify differences in absorption and disposition processes that may underlie species variations in response to fixed dosage of a drug. These studies provide a basis for the selection of a test species from which pharmacokinetic information could be extrapolated to humans. Using certain marker (test) substances, pharmacokinetic techniques can quantify the activity of metabolic pathways or efficiency of excretion processes. The prediction of preslaughter withdrawal times for drug products developed for use in the foodproducing animals represents an application of pharmacokinetics in the field of drug residues. This application requires use of an appropriate compartmental model and the validity of the assumption that the decline in plasma concentrations parallels the rate of removal of the drug from edible tissues and organs (Mercer et al. 1977). When avid binding to selective tissues occurs, such as aminoglycosides to renal cortex, the plasma t'/2 may not reflect the gradual removal of the tissue bound drug. This represents a serious shortcoming of the use of t'/2 in predicting preslaughter withdrawal time. In drug residue studies the pharmacokinetic behaviour of the drug must be determined at both ends of the range of recommended dosage. A disproportionate increase in tissue residue concentrations with an increase in dosage of a drug is evidence that the drug shows nonlinear pharmacokinetic behaviour. Importantly, insight into the drug residue profile can only be obtained by linking fixed-dose pharmacokinetic studies of whole blood or plasma concentrations with measurement of the amount of drug in selected tissues and organs of the target species. This approach to establishing the residue profile and predicting withdrawal times has an economic aspect. It leads to a considerable reduction in the number of animals required for residue studies.
2. Pharmacokinetic Parameters Clearance (CL) measures the ability of the body to eliminate the drug. Volume of distribution (Vd) denotes the apparent space available in both the
Clin. Pharmacokinel. 22 (4) 1992
Fig. 1. Schematic representation of central and peripheral compartment-effect models currently used in pharmacokineticpharmacodynamic modelling. Drug concentrations (C) are used to calculate the fractional effect (EjE max ), employing the Langmuir equation [EjEmax = Cj(C ss 50 + c)1. Css 50 is the steady-state concentration at which a half-maximal effect is seen (from Colburn 1987, with permission).
systemic circulation and tissues of distribution to contain the drug. CL is expressed in units of flow, rather than time, and thus is a poor indicator of drug persistence in the body. Since t.;, and mean residence time (MR T), which is the statistical moment analogy to t'l2, describe drug elimination in units of time, they show drug persistence. When a drug is administered orally or by a nonvascular parenteral route (e.g. intramuscular or subcutaneous) the systemic availability (F), or fraction of the dose that reaches the systemic circulation unchanged, is an essential parameter. After these modes of administration, the absorption process affects the t.(, and MRT of the drug. Accordingly, the values obtained for these parameters are apparent rather than true. The roles and the relative merits of compartmental and noncompartmental modelling in phar-
macokinetics have recently been reviewed by Gillespie (1991). In domestic animals, as in humans, the disposition of most drugs can be analysed in terms of a 2- (generally) or 3-compartment open model. Model selection must be based on the plasma concentration-time data obtained in each individual animal. Perhaps the most common error in compartmental pharmacokinetic analysis is overestimation of the terminal exponent (on which t'l2 is based). This occurs either with sampling for too short a time or when the analytical procedure is insufficiently sensitive to measure drug plasma concentrations during the true elimination phase. A significant consequence of this error is that the plasma concentration at steady-state produced by multiple-dose therapy will differ from that predicted. Also, the predicted preslaughter withdrawal time may be erroneous.
2.1 Species Variations in Drug Elimination Species variations in pharmacokinetic behaviour can generally be attributed to differences in the rate of elimination of the drug. Although the contribution of various metabolic pathways may vary considerably across species, the fraction of the dose eliminated by metabolism may be within a somewhat narrow range. The metabolism of lidocaine (lignocaine) in the rat, guinea-pig, dog and human serves as a useful example. The contribution of any single pathway to the metabolism of lidocaine varied among these species by up to 100fold, while the total urinary excretion including unchanged drug (53.8 to 85%) varied by less than 2fold (Keenaghan & Boyes I cJ72). Although the activities of oxidative, reductive and hydrolytic reactions vary unpredictably among the domestic animal species, certain synthetic reactions are either defective or absent in some species (table II). The cat synthesises glucuronide conjugates slowly, since cats have little hepatic microsomal glucuronyl transferase. A similar situation applies to human infants and neonatal animals. The t'l2 values of drugs that undergo extensive hepatic metabolism vary widely among the species of domestic animals and humans (table III). In general, the herbivorous species (horses and ruminant species) metabolise lipid-soluble drugs more rapidly than do carnivorous species (dogs and cats). Still, there are notable exceptions to this trend, such as theophylline in horses and phenylbutazone in cattle, that defy explanation. On the basis of t'h values, humans metabolise drugs more slowly than do domestic animals. It has been suggested (Boxenbaum 1982) that the lesser quantitative ability of humans to metabolise many drugs may be correlated with their enhanced longevity. Plasma
phenazone t'h is a useful index of the rate of hepatic metabolism (microsomal oxidation) of a variety of drugs. However, it does not reflect the activity of all hepatic microsomal metabolic pathways (Vesell et al. 1973). Comparison of the 24h cumulative urinary excretion of trimethoprim shows less than 5% of a dose excr~ted unchanged in ruminants (cows and goats). The corresponding proportions are 10% in horses, 20% in. dogs and 47% in humans. Species differences in the combined activity of the elimination processes for trimethoprim reflect the t'h values of the drug (0.7 to 1.5, 3.2, 4.6 and 1O.6h in ruminants, horses, dogs and humans, respectively) [Prescott & Baggot 1988]. Among the ruminants, sheep have a hepatic microsomal protein content significantly higher than that of cattle or goats and there is no correlation between the concentration of hepatic microsomal cytochrome P450 and activity of the enzymes that catalys.e Phase I biotransformation reactions (Dalvi et al. 1987). The t'h values of some drugs eliminated by hepatic metabolism are shorter (by about 2-fold) in goats than in cattle. Pygmy (dwarf-like) goats metabolise phenazone (microsomal oxidation), sulphonamides (hydroxylation) and chloramphenicol (glucuronide synthesis) more rapidly than other breeds. This observation is significant because of the notion that pygmy goats can be used as an animal model to represent ruminant species. For drugs with a low hepatic extraction ratio [blood CL/liver blood flow < 0.02], intrinsic clearance (CLint) may be the parameter of choice in interspecies comparison of hepatic drug metabolism rates. CLint estimates the activity of the hepatic drug-metabolising enzymes. Drugs that undergo extensive hepatic metabolism and have a low extraction ratio include phenazone (marker substance), valproic acid, phenytoin, theophylline and
Table II. Species with a defective metabolic pathway (synthetic reaction) [adapted from Baggot 1977] Species
Type of defect
Cat Pig Dog
Glucuronide synthesis Sulfate conjugation Acetylation
-OH. -COOH. -NH2. =NH. -SH Aromatic -OH. -NH2 Aromatic -NH2
Slow rate Low extent Absent
Clin. Pharmacokinet. 22 (4) 1992
Table III. Species variations in the half-life of drugs eliminated mainly by hepatic metabolism (Baggot 1977, updated with unpublished data)
Half-life (h) ruminant species
Amphetamine Diazepam Ketamine Metronidazole Pentobarbital Phenazone (antipyrine) Phenylbutazone Phenytoin Sulfadiazine Sulfadimethoxine Theophylline Thiopental Trimethoprim a b c d e
0.6 1.0 2.8 0.8 3.1d 43.09 2.5 7.9-8.6 6.9 3.3 0.7-1.5
1.4 9.7 0.7 3.9 1.5 2.8 4.1-4.7 8.2 3.6 11.0 14.8
4.58 •b 8.0 1.0 4.5 4.5 3.2 2.5-6 6.0 5.6 13.2 5.7 8.5 4.6
10-158 ,b 43.0 2.5 8.5 22.3 10.3-12.7 72.0e 24.0e 7.0 40.0 9.0 11.5 10.6b
Half-life is markedly influenced by urinary pH. More than 30% is excreted unchanged in the urine. Half-life is dose-dependent. Half-life of phenazone in camels is 18.8h (Elsheikh et al. 1991). Cattle.
rifampicin. Since the CLint of phenazone in humans is approximately one-seventh of that in many other species (Boxenbaum 1980), it seems that hepatic microsomal oxidation is least active in humans. Renal excretion is the principal process of elimination for drugs that are predominantly ionised at physiological pH and for compounds (polar drugs and drug metabolites) with limited lipid solubility. Inulin CL provides a useful measure of glomerular filtration rate (GFR), which varies between species. For example, inulin CL (in ml/min/kg) is 1.66 in horses, 1.84 in cows, 2.26 in sheep and goats, 3.51 in cats and 3.96 in dogs (corresponding values in L/h/kg are 0.10, 0.11, 0.14, 0.21 and 0.24, respectively) [Baggot 1977]. On the basis ofGFR, the t'/2 values of those drugs eliminated solely by glomerular filtration (e.g. aminoglycosides) will be shorter in dogs and cats than in horses, if the Vd is similar in the different species. The average t'/2 of gentamicin, for example, is 1.25h in dogs and cats and 1.85h in horses (Prescott & Baggot 1988). This difference in t'/2 is unrelated to urinary pH.
Although GFR is lower in birds than in animals, the t'/2 of gentamicin in turkeys is 2.57h (Pedersoli et al. 1989) and in birds of prey is in a range (1.35 to 2.46h) similar to that in mammals (Dorrestein et al. 1984). For comparative purposes, the average t'/2 of gentamicin in gopher snakes maintained at ambient temperature (24°C) is 82h (Bush et al. 1978). Evaluation of species differences in pharmacokinetics may be simplified by using double logarithmic allometric plots and Dedrick plots. For some drugs that are entirely renally eliminated, allometric scaling of animal data (mouse, rat, monkey and dog) can be used to predict human pharmacokinetic values (Mordenti 1985). Serum doxycycline concentration-time profiles and elimination t'/2 values in several species (including humans) were evaluated by allometric techniques (Riond & Riviere 1990). The elimination t'/2 increased with bodyweight. Doxycycline is mainly eliminated by nonrenal excretion. The basis of species variations in the t'l2 of drugs eliminated by both metabolism and excretion could
be ascribed to differences in metabolic pathways and the influence of urinary pH on the extent of renal tubular reabsorption of unchanged drug. In any species, urinary pH depends mainly on diet. The usual pH of the urine of carnivores is acidic (pH 5.5 to 7), while that of herbivores is alkaline (pH 7 to 8) [Baggot 1977]. In humans, the urine is generally acidic, but can vary over a wide pH range (4.5 to 8.2). Since plasma pH is maintained within a narrow range (7.3 to 7.5), a large pH gradient may exist between plasma and urine. This gradient influences the extent of reabsorption of weak organic electrolytes with pKa values in the range of urinary pH and thereby changes the rate of their elimination. The consequence of the urine pH-elimination rate effect is greatest in humans. This is because a larger fraction of the dose is excreted unchanged in urine of humans than of animals, particularly herbivores. The comparative pharmacokinetics of amphetamine serve as a useful example (Baggot & Davis 1973; Beckett & Rowland 1965).
ilar disease conditions in humans and animals. The nature of pathophysiological changes affecting disposition is likely similar, but the quantitative effect of these changes can be expected to vary among species. Thus, it is not valid to extrapolate recommendations on dosage adjustment. Pharmacokinetic studies in animals provide useful information on parenterally administered drugs, but this information relates mainly to the species studied. The bioavailability of drugs from oral dosage forms can often be extrapolated from dogs, but not from herbivores, to humans, depending on the formulation and the influence of food. Note that when determining the bioavailability of drugs in dogs with a view to extrapolating the data to humans, it is useful to fast the dogs for l2h before drug administration. This procedure should be stated in the research report. Many such studies can be criticised for failing to take account of feeding regimens.
2.2 Extrapolation from Animals to Humans
The route of administration of a drug for veterinary use may be governed by the available dosage form and the objective of therapy. The volume and mass (solid dosage forms) of the dosage form and the convenience of the dosage interval are im-
The validity of extrapolating pharmacokinetic data from animals to humans depends largely on the mechanism of elimination of the drug. For extensively metabolised drugs, the contribution of the various metabolic pathways generally differs and the overall elimination rate may vary widely across species. Humans metabolise most lipid-soluble drugs more slowly than animals. Thus, a larger fraction of the dose is excreted unchanged in the urine of humans than of animals, particularly the herbivores. Intersubject variation is usually wider in humans than in any animal species of a similar group size. This may be partly because most animals in an experimental group are relatively homogeneous in terms of age, diet, bodyweight and size and are maintained in a more controlled environment. Humans, in contrast, have exceedingly varied dietary habits and are exposed to a wide range of environmental chemical substances. To my knowledge, there are no data available on the changes in drug disposition induced by sim-
• = Ampikel-20® o = Polyflex® • = Penbritin® 0= Duphacillin" .&
10 11 122748 Time (h)
Fig. 2. Mean plasma ampicillin concentrations in ruminant calves after intramuscular injection of 5 parenteral ampicillin preparations at similar dose levels (7.7 ± 1.0 mgJkg) [from Nouws et al. 1982, with permission).
Clin. Pharmacokinet. 22 (4) 1992
portant in selecting a formulation for drug administration to animals. Besides species variations in dosages (systemically available dose/dosage interval), the wide (250-fold) range of bodyweights makes the development of veterinary dosage forms difficult. Bodyweight variations mean that human oral dosage forms cannot generally be administered intact to animals other than medium to large sized dogs. The lack of availability of suitable dosage forms often limits application of the most appropriate drug therapy in domestic animals.
Table IV. Mean ± SO (range) of pharmacokinetics of gentamicin in Thoroughbred horses after intramuscular injection of 2 strengths of parenteral gentamicin sulfate administered in a dose of 5 mg/kg (Baggot, unpublished data) Pharmacokinetic parameter
'Gentocin' (5% solution)
'Gentaject' (10% solution)
t'l2. (h) Gmax (mg/L) t max (h) t'htl (h) AUG (mg/L' h)
0.33 ± 0.16 19.0 ± 11.2 0.875 (0.5-1.5)8 2.10,± 0.67 78.5 ± 33.0 (32.9-127.7)
0.44 ± 0.31 20.1 ± 10.9 1.0 (0.5-1.5)a 1.81 ± 0.32 76.4 ± 27.8 (34.1-113.9)
3.1 Parenteral Administration
Abbreviations: t\l2a = absorption half-life; Gmax = peak plasma
concentration; t max time to Gmax; "/2,8 apparent half-life; AUG = area under the plasma concentration-time curve.
The suitability of a parenteral drug preparation for administration to a particular animal species depends on the concentration of active drug and the formulation of the product. The influence of formulation on drug bioavailability and plasma concentrations was shown after intramuscular administration of 5 different parenteral ampicillin formulations to ruminant calves (Nouws et al. 1982). Intramuscular injection of 'Ampikel-20' or 'Poliflex' into the lateral neck region resulted in 100% bioavailability of ampicillin, but the shapes of the plasma concentration-time curves were dif• = 0= • = o= ... =
0 0 0
M. serratus M. biceps M. pectoralis M. gluteus Subcutaneous
E II) til
0:: 0 0
5 Time (h)
Fig. 3. Mean plasma procaine-penicillin concentration-time curves after administration of 20 OOOU/kg of the antibiotic to 5 animals (4 horses and I pony) at 5 different injection sites (from Firth et al. 1986, with permission).
ferent (fig. 2) and the apparent t'h values of the drug were 2.1 ± O.5h (,Ampikel-20') and 3.8 ± l.7h ('Polyflex'). 'Albipen' and 'Duphacillin' yielded much lower plasma ampicillin concentrations, which persisted for 3 to 6 days and had apparent t'h values of 22.2 ± 7.6h and 11.9 ± 3,7h, respectively. 'Penbritin' bioavailability and apparent t'/2 were intermediate between the 2 groups of ampicillin preparations. Location of the injection site may affect the systemic availability and peak plasma concentration (Cmax) of drugs administered as aqueous suspensions or sustained release parenteral preparations. This was shown in a study of plasma concentration profiles for procaine-penicillin (penicillin G procaine) administered as procaine-penicillin to horses (fig. 3), In descending order, the systemic availability and Cmax of procaine-penicillin were highest after intramuscular injection in the neck, followed by intramuscular injections to the biceps, pectoralis and gluteus, and subcutaneous injection in the cranial part of the pectoral area (Firth et al. 1986). Injection site-related variations in bioavailability might not apply to parenteral solutions that provide rapid absorption of the drug. When gentamicin 3 mg/kg was administered intramuscularly or subcutaneously to dogs, bioavailability (93.92 to 96.65%) and gentamicin Cmax (9.43 to 10.89 mg/
L) were independent of injection site (Wilson et al. 1989). Gentamicin sulfate 5% administered to horses intramuscularly in the cervical serratus ventralis muscle or subcutaneously provided similar plasma gentamicin concentrations and areas under the plasma concentration-time curves (AUC) that did not differ significantly (Gilman et al. 1987). Comparison of gentamicin sulfate 5% or 10% parenteral preparations administered intramuscularly to Thoroughbred horses at the same dose (5 mgf kg) resulted in similar plasma concentration-time profiles, AUC values, absorption and elimination pharmacokinetics (table IV). These 2 gentamicin preparations are each 100% bioavailable (Baggot, unpublished data). 3.2 Oral Administration Diet is a useful basis on which to group species of domestic animals when comparing gastrointestinal drug absorption. Absorption in carnivorous species (dogs and cats) is thought to resemble that in humans, with drugs absorbed by passive nonionic diffusion mainly from the upper small intestine. The herbivorous species (horses and ruminant animals) differ markedly from carnivores in anatomical arrangement of the gastrointestinal tract. Nevertheless, drug absorption is also by passive nonionic diffusion in these species (Baggot 1977). There are, however, wide differences in the pattern of drug absorption between horses, ruminants (cattle, sheep and goats) and carnivores.
The horse, like the human, dog and cat, is monogastric but differs from other species in that microbial digestion of polysaccharides takes place in the specialised caecum and colon. In ruminants, bacterial fermentation takes place continuously in the reticulorumen, a voluminous forestomach lined with stratified squamous epithelium. Comparative studies in herbivorous species have shown that the drug metabolising capacity of the liver is greater and systemic availability of orally administered drugs is lower than in humans, dogs and cats. Oral absorption of drugs may be influenced by drug release from the dosage form, stability of the drug in the stomach or rumen and the degree of ionisation and lipid solubility. Incomplete systemic availability of orally administered drugs also may be due to metabolism in the intestinal mucosa or liver before reaching the systemic circulation ('first-pass' effect). These factors exemplify the bioavailability of orally administered drugs in dogs (table V). The bioavailability of metronidazole 250mg, administered intravenously or via a nasogastric tube as an aqueous suspension of crushed tablets, was determined in unfed Quarterhorse mares using a randomised crossover design (Baggot et al. 1988b). The drug was well absorbed (74.5 ± 13.0%) from the gastrointestinal tract and the absorption rate varied widely among individual horses (table VI). Similarly, in Beagle dogs the systemic availability of metronidazole 250mg tablets was high and varied from 59 to 100% across individuals (Neff-Davis
Table V. Some drugs which undergo presystemic elimination in the dog (adapted from Baggot 1988)
Diazepam Flunitrazepam Levodopa Lidocaine (lignocaine) Phenytoin Propranolol Salicylate
Tablet Micronised, gelatin capsule Gelatin capsule Solution Tablet, capsule, suspension Tablet Aspirin tablet
2 2 25 10 30 80mg 250mg
Abbreviations: F = bioavailability.
44 15 43-54 2-17 45
Site of metabolism
Gut wall and liver Gut wall and liver Gut lumen or gut wall (or both) Liver Liver Liver Gut wall and liver
Clin. Pharmacokinet. 22 (4) 1992
Table VI. Pharmacokinetics of metronidazole 20 mg/kg administered via nasogastric tube to Quarterhorse mares (n = 6) [Baggot et al. 1988b]
Mean ± SD
Lag time (h) MAT (h) emax (mg/L) t max (h) t'l,# (h) MRT (h) F(%)
0.30 a 3.38 ± 4.09 21.2 ± 3.1 1.5a
0-0.88 0.41-11.20 16.7-24.3 0.7-4.0 4.21-11.79 6.69-18.06 58.4-91.5
6.0 ± 2.94 9.41 ± 4.32 74.5 ± 13.0
a Median. Abbreviations: MAT = mean absorption time; max = peak plasma concentration; t max = time to max ; t'l,p = apparent halflife; MRT = mean residence time; F = bioavailability (corrected for intrasubject variability in the elimination rate).
et al. 1981). In horses, the MRT (6.02 ± 0.91h) after intravenous administration was used to calculate mean absorption time (MAT). In estimating the bioavailability (F) of metronidazole, a correction (k&A2) was made for intrasubject variability in the rate of elimination, where kd is the disposition (apparent elimination) rate constant following oral administration and A2 is the elimination rate constant following intravenous administration. In this correction it is assumed that any change in the rate of elimination from 1 phase of the study to the next reflects only a change in CL of the drug. In horses, the time of feeding relative to oral
administration affects the absorption of some drugs. When oral rifampicin 5 mg/kg was administered to horses Ih after feeding, bioavailability was 25.6% compared with 67.6% when administered Ih before feeding (table VII) [Wilson et aI., personal communication]. Absorption was preceded by a short lag time and its rate was not influenced by the time of feeding. The administration of phenylbutazone 4.4 mg/ kg, as an aqueous suspension of a granular (powder) formulation, to Welsh Mountain ponies yielded marked variation in the time to C max (t max ) with different feeding schedules (Maitho et al. 1986). When access to hay was permitted before and after administration, the mean t max was 13.2 ± 1.2h and double peaks in the plasma concentration-time curve were common. Double peaks also occurred when phenylbutazone was given to ponies deprived of food before and allowed access to hay after administration. In this circumstance, the t max was earlier (3.8 ± 1.3h after morning administration and 5.3 ± 1.5h following afternoon administration). Absorption of the drug was more regular and double peaks were less apparent when food was withheld both before and after administration. It was postulated that, while some of the dose may be absorbed in the small intestine, some may be adsorbed on to the feed and be subsequently released by fermentative digestion to be absorbed in the colon and/or caecum. Delayed absorption of
Table VII. Influence of the relationship between the time of feeding and oral administration of rifampicin 5 mg/kg on the pharmacokinetics of the drug in horses (n = 5) [Wilson et aI., personal communication]
Lag time (h) MAT (h) emax (mg/L) t max (h) t'l,# (h)
MRT(h) F(%) a Median (range). Abbreviations: see table VI.
Time of administration 1h before feeding
1h after feeding
0.28 (0.22-0.49)a 2.80 ± 1.47 3.30 ± 1.42 1.5 (1-4)a 7.26 ± 1.78 9.32 ± 1.96 67.6 ± 25.8
0.27 (0.11-0.52)a 2.48 ± 1.19 1.21 ± 1.10 2.25 (1-5)a 6.91 ± 0.90 9.00 ± 0.68 25.6 ± 17.20
phenylbutazone in ponies allowed free access to hay was not accompanied by a significant reduction in the extent of absorption. Systemic availability was estimated to be 69% in fed and 78% in unfed ponies. 3.3 Prolonged Release Products Prolonged release oral drug products offer an alternative to continuous intravenous infusion, which is generally impractical in domestic animals, by maintaining plasma concentrations within the therapeutic range for an extended duration. These products may be either sustained release (SR) or controlled release (CR) delivery systems. The fluctuation in plasma concentrations at steady-state depends on the dosage interval and the till of the drug (Theeuwes & Bayne 1977). The apparent t'/2 of the drug will reflect the rate of release from a prolonged release dosage form rather than the rate of elimination ('flip-flop' phenomenon). Furthermore, fluctuation in steady-state plasma concentrations (Cmax/Cmin ratio) will be decreased (Cheung et al. 1988). The convenience afforded by less frequent administration is an important practical advantage of prolonged release products over conventional dosage forms. In monogastric species (humans, horses, dogs and cats) the residence time of an oral dosage form in the small intestine (estimated to be 9 to 12h) limits the duration of sustained release. This suggests that the dosage interval should be 12h (or 24h). In horses, if an SR product passes intact into the large intestine, a 24h interval should be recommended, although this could delay the attainment of effective plasma drug concentrations. The pharmacokinetics of theophylline were determined in horses following oral administration of immediate release (conventional) aminophylline tablets or SR theophylline tablets (TheoDur®) and intravenous administration of a solution (Goetz et al. 1989). Theophylline absorption was slower and MR T was longer following administration of the SR dosage form (table VIII). Absolute bioavailability was 87.4 ± 5.8% for the immediate release tablets and 97.8 ± 11.15% for the SR tablets. A loading dose of 20 mg/kg followed by 15 mg/kg
Table VIII. Mean (± SO) pharmacokinetics (n = 6) of theophylline following oral administration of conventional aminophylline tablets (CT) and sustained release theophylline tablets (SRT) to horses (Goetz et al. 1989)
Dose (mg/kg) MAT (h) Cmax (mg/L) t max (h) MRT (h) F(%)
9.94 0.10 ± 1.25 11.51 ± 1.38 1.62 ± 0.59 13.8 ± 2.8 87.4 ± 5.8
20.0 4.45 ± 1.39 17.20 ± 1.27 7.33 ± 1.03 18.2 ± 2.3 97.8 ± 11.15
Abbreviations: see table VI.
every 24h administered as SR tablets should decrease fluctuation in steady-state plasma concentrations (within the range 6 to 17 mg/L). Following the intravenous administration of a parenteral preparation oftheophylline the MRT was 13.74 ± 2.45h in horses (Goetz et al. 1989) and 7.47 ± 1.02h in Beagle dogs (Koritz et al. 1986). Absolute bioavailability was 91 ± 6% from conventional aminophylline tablets and varied from 30 ± 16% to 76 ± 18% after administration of 4 different sustained release oral dosage forms to Beagle dogs (Koritz et al. 1986). Although MAT and MRT values did not differ significantly (p > 0.05) between the SR dosage forms, the dosage regimen for anhydrous theophylline tablets (TheoDur®), 20 mg/kg every 12h, was predicted to maintain plasma theophylline concentrations within the therapeutic range (10 to 20 mg/L) and to provide the least fluctuation in the ratio of maximum to minimum steady-state plasma concentrations. Palatable oral paste preparations are both convenient to administer and readily accepted by horses. Although some oral pastes are currently available (e.g. trimethoprim/sulphadiazine, ivermectin, phenylbutazone), it remains to be determined whether these preparations provide sustained release of their active constituents. Due to the high activity of hepatic microsomal-associated metabolic pathways in horses, the 'first-pass' effect could substantially decrease systemic availability of drugs that undergo extensive hepatic metabol-
Clin. Pharmacokinet. 22 (4) 1992
ism. This is particularly the case when they are administered as SR oral dosage forms. Allowance should be made for first-pass metabolism by increasing the strength (mg) when formulating oral preparations. In ruminant species the rumen is anatomically well located for accommodating SR or CR oral boluses. Dissolution is the rate-limiting step controlling release and absorption of sulphamethazine from available SR oral dosage forms. CR delivery systems have been developed for certain anthelmintic drugs. They include the Paratect® bolus (contains morantel) and the Ivomec® bolus, using the ALZET mini-osmotic pump for intraruminal ivermectin delivery. These oral dosage forms release drug at a constant rate over a 90-day period. Autoworm® and Multidose 130® release pulse doses of oxfendazole at about 3-week intervals (Jacobs et al. 1987; Rowlands et al. 1988). This interval roughly coincides with the prepatent period of the major tristrongylids of cattle. After releasing their drug content, these delivery devices remain lodged in the reticulorumen. CR systems, unlike SR boluses, are depleted of drug at the end of the stated delivery period. This is an important consideration in the avoidance of residual levels in the edible tissues of food-producing animals.
4. Changes in Drug Disposition Little is known about the effect of disease and altered physiological states on the pharmacokinetics of drugs in animals.
The decreased CL of indocyanine green in 10 horses fasted for 72h (1.58 ± 0.57 mlfmin/kg) [0.09 ± 0.03 L/h/kg] compared with fed (3.53 ± 0.67 mlfmin/kg) [0.21 ± 0.04 L/h/kg] supports the hypothesis that reduced hepatic organic ion uptake is the underlying cause of the hyperbilirubinaemia that accompanies fasting (Engelking et al. 1985). CL values for phenazone and paracetamol (acetaminophen) in horses (Engelking et al. 1987) and chloramphenicol in pygmy goats (Abdullah & Baggot 1986a) were reduced by fasting for 72h. Since Vd values remained unchanged, the t1;' values of these substances were correspondingly increased. The calculation of digoxin dosage during renal failure, based on the correlation between CLcR and the elimination rate constant of the drug, is complicated by the observation that the Vd is decreased during this state (Jusko et al. 1974; Reuning et al. 1973). Changes in digoxin disposition were evaluated in the same mongrel dogs before and after experimentally inducing chronic azotaemia (Gierke et al. 1978). In the azotaemic condition, the CLR, CL and Vd of digoxin were significantly decreased. Altered distribution, which was accompanied by a corresponding increase in the apparent volume of the central compartment (Vd of the pharmacokinetic model describing the disposition of digoxin, was attributed to decreased tissue (muscle) binding of the drug. There was a poor correlation (r = 0.38) between CLCR, which was significantly decreased (n = 7; mean ± SD 2.15 ± 0.52 to 0.78 ± 0.25 mlfmin/kg) [0.13 ± 0.03 to 0.05 ± 0.02 L/h/kg],
Table IX. Mean ± SO pharmacokinetics of intravenous imidocarb 4 mg/kg in healthy and febrile goats (Abdullah & Baggot 1986b) Parameter
Normal (n = 8)
CL (ml/min/kg) (min) Vd area (ml/kg) Vss (ml/kg)
1.62 ± 251 ± 544 ± 492 ±
IBR (n = 6)
ECE (n = 6) 0.50 94 88 82
0.76 ± 370 ± 322 ± 222 ±
0.28 391 183 29
0.92 ± 208 ± 276 ± 257 ±
TEl (n = 6) 0.09 31 49 41
4.10 ± 254 ± 1398 ± 1295 ±
1.20 91 351 333
Abbreviations: ECE = fever induced by Escherichia coli endotoxin; IBR = fever induced by infectious bovine rhinotracheitis virus infection; TEl = fever induced by Trypanosoma evansi infection; CL = total body clearance (to convert to L/h/kg multiply by 0.06); t'l2 = elimination half-life; Vd area = volume of distribution calculated using the area method; Vss = volume of distribution at steadystate.
Table X. Mean ± SD pharmacokinetics of intravenous imidocarb 4 mg/kg in healthy and febrile dogs (Abdullah & Baggot 1984) Parameter
Normal (n = 7)
ECE (n = 6)
TEl (n = 6)
1.47 ± 0.38 207 ± 45 432 ± 109 390 ± 92
0.89 ± 0.33 198 ± 38 250 ± 86 188 ± 61
2.21 266 822 722
tv, (min) Vd area (ml/kg) Vss (ml/kg)
± ± ± ±
0.49 73 221 202
Abbreviations: see table IX.
and the elimination rate constant of digoxin. This is consistent with the observation that, unlike in humans, there is a substantial nonrenal component (""45% of the dose) to digoxin elimination in dogs. Although the tl;' of the drug was prolonged during azotaemia in 6 of the 7 dogs used in the study, it was not significantly increased (28.0 ± 4.0h in normal dogs; 36.2 ± ll.5h during azotaemia) [Gierke et al. 1978]. The effect of fever on serum concentrations of gentamicin following administration of single doses was studied in dogs and humans (Pennington et al. 1975). Escherichia coli endotoxin-induced fever in dogs resulted in a decrease of approximately 25% in serum drug concentrations 30 and 60 min after an intravenous dose of gentamicin 1.5 mg/kg when compared with corresponding values when afebrile. In 6 healthy volunteers with etiocholanolonestimulated fever, serum gentamicin concentrations were reduced by an average of 40% in samples collected I, 2 and 3h after an intramuscular injection of gentamicin 1.5 mg/kg when compared with the concentrations in the same individuals when afebrile. Although serum gentamicin concentrations were lower during the febrile state, the tl;' and CLR of the antibiotic were not significantly changed. The effect of fever could be attributed to increased extravascular distribution of the antibiotic. Fever induced by E. coli endotoxin or infectious bovine rhinotracheitis (IBR) virus infection produced similar changes in pharmacokinetic parameters describing the disposition of imidocarb (an antiprotozoal drug) in goats (Abdullah & Baggot 1986b). The changes induced by Trypanosoma evansi infection were distinctly different (table IX).
The pattern of changes in the pharmacokinetics of imidocarb caused by these disease conditions was similar in febrile dogs (table X; fig. 4). During the febrile stage of the various disease conditions statistically significant changes occurred in the Vss and CL of the drug, while the tl;' did not change significantly (Abdullah & Baggot 1984, 1986b). Halothane anaesthesia alters the disposition of intravenous gentamicin 4 mg/kg in horses (Smith et al. 1988). Compared with unanaesthetised animals, halothane caused significant decreases in the CL (p < 0.01) and Vd (p < 0.05) of gentamicin
o § .~
= E. coli endotoxin
0= Healthy !':, = T. evansi
2 10~-'---2r--'3--~4--~5r--r6--;7r--r- Time (h)
Fig. 4. Mean plasma imidocarb concentration-time curves in 7 healthy dogs and 6 febrile dogs (with fevers caused by Escherichia coli endotoxin or Trypanosomiasis evansi infection) after administration of single intravenous doses of 4 mg/kg (data from Abdullah & Baggot 1984).
Clin. Pharmacokinet. 22 (4) 1992
Table XI. Mean ± SEM pharmacokinetics of intramuscular xylazine premedication 0.2 mg/kg on the disposition of intravenous ketamine 5 mg/kg and duration of anaesthesia in 4 female ruminant calves (Waterman 1984) Parameter
Ketamine pius xylazine
CL (ml/min/kg) t'h (min) Vd area (L/kg) Anaesthesia duration (min) [range]
40.39 ± 6.6 60.5 ± 5.4 4.04 ± 0.66 9.8 ± 1.7 [6-14]
21.25 ± 54.2 ± 1.41 ± 22.3 ± [17-26]
p < 0.05 NS P < 0.01 p < 0.01
5.4 11.4 0.32 2.5
= not statistically significant; for other abbreviations see table
and a significant increase in the t'l2 (p < 0.05) of the drug. The prolonged t'l2 (4.03 ± 1.69h in halothane-anaesthetised horses; 2.0 I ± 0.35h in the same horses unanaesthetised) could be attributed mainly to decreased CL of the drug, due to the effect of halothane on renal blood flow. In xylazine premedicated female ruminant calves the duration of ketamine anaesthesia was significantly (p < 0.01) prolonged (table XI). This effect was associated with significant decreases in both the Vd area and the CL of ketamine, while the t'l2 did not change significantly.
5. The Neonatal Period Differences between neonatal and adult animals in the intensity and duration of the effects produced by a drug can generally be· attributed to altered disposition. These alterations affect the plasma drug concentration-time profile and the concentrations attained at drug receptor sites and account for the clinical observation that neonatal animals are often more 'sensitive' to the effects of drugs. Some characteristics of the neonatal period include better absorption from the gastrointestinal tract, lower binding to plasma proteins, increased Vd of drugs that distribute in extracellular fluid or total body water, increased permeability of the blood-brain barrier and slower elimination (longer t'l2) of most drugs. The altered absorption and disposition can often be accommodated by adjusting the usual (adult) dosage. However, the meagre pharmacokinetic data available on drugs in neo-
natal animals limits the dosage recommendations that can be made. This is further complicated by interspecies variation in the rate at which the physiological processes affecting drug absorption and disposition mature. The neonatal period (generally the first month of postnatal life) appears to vary among species from I week in foals (Baggot & Short 1984) to 6 weeks in calves and puppies. 5.1 Absorption Colostral antibodies (macromolecules) are absorbed from the gastrointestinal tract during the first 24h after birth. This suggests that the intestinal epithelium is more permeable during this short period and that poorly absorbable drugs could be absorbed. The pH of gastrointestinal contents also influences drug absorption. At birth, the pH in the stomach and upper small intestine of the foal is relatively high but decreases with ingestion of milk and as the secretion of pepsin increases. It follows that drugs, particularly weak organic bases, may be better absorbed at this time. The gastrointestinal surface area, mucosal enzyme activity and portal venous blood flow increase during this period and, perhaps more significantly, the microflora of the caecum and colon become established. Antimicrobial agents, such as penicillins, are poorly absorbed and cause digestive disturbances in older foals and adult horses. Yet some penicillins can be administered orally to neonatal and young foals to treat systemic bacterial infections caused by susceptible microorganisms (based on minimum inhibitory concentrations). For example, oral amox-
icillin trihydrate 30 mg/kg produced serum amoxicillin concentrations above 1 mg/L for 6h in 5- to 10-day-old foals (Love et al. 1981). Systemic availability was 30 to 50% in the foals compared with 5 to 15% in adult horses (Baggot et al. 1988a). Drugs that undergo extensive 'first-pass' metabolism (in the intestinal mucosa and the liver) should have higher systemic availability in neonatal animals; trimethoprim is an example. Since the rumen takes 8 to 12 weeks to develop and become functional, the bioavailability profile of drugs administered orally to neonatal calves should be similar to that in monogastric species. Chloramphenicol, for example, administered as an oral solution is well absorbed in neonatal (preruminant) calves, and oral administration of25 mg/ kg at 12h intervals will maintain therapeutically effective plasma concentrations (>5 mg/L) of the antibiotic (Huffman et al. 1981). In older calves and adult cattle, oral administration of chloramphenicol fails to produce effective plasma concentrations, since the antibiotic is inactivated (reductive reaction) in the rumen. 5.2 Distribution Changes in body composition may largely account for species variations or age-related differences in the distribution pattern of drugs. Total body water may comprise 75% of bodyweight in neonatal animals compared with 50 to 60% in adults (Caprile & short 1987; Vaale 1985). Extracellular fluid volume made up 43% of bodyweight in l-week-old foals, whereas it constituted 34% in
3-week-old foals (Kami et al. 1984). The extracellular fluid volume accounts for 22% of the bodyweight of horses. The larger volume of extracellular fluid in neonatal foals is consistent with higher Vd values of drugs that are highly ionised in plasma or are relatively polar (such as penicillins, aminoglycosides and nonsteroidal anti-inflammatory drugs). Plasma concentrations of these drugs will be lower, while higher concentrations may be attained at drug receptors or sites of bacterial infection. There is a considerably smaller age-related change in body fat content in horses than in other species. Total body fat normally constitutes 2 to 3% of bodyweight in neonatal foals compared with 5% in horses. 5.3 Metabolism Although there are species differences in the degree to which some drug metabolising pathways are deficient in neonatal animals, a relative lack of development of hepatic smooth-surfaced endoplasmic reticulum and its associated drug metabolising enzyme systems (oxidative reactions and glucuronide conjugation) appears to be a characteristic of the neonatal period in all mammalian species. Because of the low activity of these metabolic pathways, particularly during the first 24h after birth, many drugs (salicylate, trimethoprim, chloramphenicol, theophylline, phenytoin and phenobarbital) have prolonged t'l2 values during the neonatal period (Davis & Short 1973; Nielsen & Rasmussen 1976; Reiche et al. 1980; Short 1980; Short & Davis
Table XII. Mean ± SD age-related changes in the disposition of intravenous chloramphenicol SO mg/kg in calves (Reiche et al. 1980)
Abbreviations: see table IX.
Age of calves (n = S)
1.1 ± 0.24 11.7 ± 1.7 1.13 ± O.OS
1.9 ± 0.03
7.S ± 0.9
3.1 ± 0.63 4.9 ± 0.7 1.23 ± 0.06
Clin. Pharmacokinet. 22 (4) 1992
1970; Svendsen 1976). In most species (ruminant animals, pigs, dogs and presumably cats), the hepatic microsomal-associated metabolic pathways develop rapidly during the first 3 to 4 weeks after birth and at 8 to 12 weeks of age have developed activity approaching that of adult animals. The foal is an exception in the rate of development of glucuronide synthesis (the oxidative pathway has not been studied) [Adamson et al. 1991]. Phenazone showed a prolonged t1/, and low CL in newborn calves, while at 6 weeks of age the t1/, was approximately twice that in adult cattle and CL had increased 4-fold to one-half that in the adult (Depe1chin, personal communication; Depe1chin et al. 1988). The Vd did not change with age. In a study of trimethoprim disposition the t1/, was 40 min in goats and 4 to 5 times longer in newborn kids. It was concluded that a period of 40 to 50 days is required for the t1/, of trimethoprim to decrease to the value found in adult goats (Nielsen & Rasmussen 1976). Age-related changes in the disposition of chloramphenicol in calves (table XII) showed an increased capacity to metabolise the drug (Reiche et al. 1980). Increased CL was accompanied by decreased t'/2; Vss did not change. The rate of elimination of the drug increased markedly during the first week of postnatal life and at 10 to 12 weeks it was similar to that in adult cattle. The pattern of changes in the pharmacokinetics of chloramphenicol in foals is quite different from that in calves. In a study of the influence of age on the disposition of chloramphenicol in foals (1, 3, 7, 14 and 42 days of age), it was found that all 3 para-
meters (CL, t1/, and Vd) changed during the first week of postnatal life but little further change occurred between 1 and 6 weeks of age (Adamson et al. 1991). The greatest changes occurred during the first 3 days and the parameter most affected was t1/, (table XIII). The large decrease in t1/, was associated with a significant increase in CL and smaller decrease in Vd of the drug. If chloramphenicol is eliminated by glucuronidation, it would appear that this microsomalassociated metabolic pathway develops more rapidly (within the first week) in foals than in calves and other species. The paucity of information available on age-related development of metabolic pathways in foals prevents further comment. In a study of the influence of age on the rate of elimination of caffeine (eliminated by hepatic microsomal metabolism) in dogs, the t1/, decreased rapidly from 1 day of age (47.58 ± 5.35h; mean ± SEM, n = 9) to 14 days of age when it was similar to that in adult dogs (6.66 ± 0.85h; n = 6). The rapid decrease in t1/, was associated with increased CL of the drug. The interesting observation was made that in 5 puppies between 30 and 45 days old, the t1/, was significantly shorter (3.70 ± 0.53h) than in adult dogs (Warszawski et al. 1977). A similar finding was reported for various drugs in young children (Rane & Wilson 1983). Whether induction of microsomal enzyme activity occurs, the age range to which it applies and the underlying cause remain to be shown. Hormonal influences could be involved.
Table XIII. Influence of age on the mean (± SO) pharmacokinetics of intravenous chloramphenicol 25 mg/kg in foals (Adamson et al. 1991)
Age of foals (n = 6) 1 day
CL (ml/min/kg) tv, (h) Vd area (ml/kg) Vss (ml/kg) Abbreviations: see table IX.
2.25 ± 6.19 ± 1101 ± 992 ±
3 days 0.67 2.43 284 269
6.24 1.48 753 543
± ± ± ±
2.22 0.51 226 173
8.86 0.64 491 310
± ± ± ±
1.90 0.14 158 67
5.4 Renal Excretion Renal excretion is the principal process of elimination for drugs that are predominantly ionised at physiological pH (such as penicillins and cephalosporins), for polar drugs (aminoglycosides) and compounds with limited lipid solubility (drug metabolites). The renal excretion mechanisms (glomerular filtration and active, carrier-mediated tubular excretion) are incompletely developed at birth in all species of domestic animals and the human. During the neonatal period these excretion mechanisms mature independently at rates that are species-related. GFR based on inulin CL attains adult values at 2 days in calves and 2 to 4 days in lambs, kids and piglets, and may take at least 14 days in puppies. Proximal tubular secretion, based on paraaminohippurate CL, matures within 2 weeks after birth in the ruminant species and pigs, but may take at least 4 to 6 weeks in dogs. Comparable studies of the development of renal excretion mechanisms in foals have not been reported in the literature. Indirect evidence, provided by pharmacokinetic studies of some antimicrobial agents eliminated by renal excretion, suggests that renal function develops rapidly in foals (Cummings et al. 1990) at a rate similar to that in ruminant species. Although renal function is immature in neonatal, particularly newborn, animals it is adequate to meet physiological requirements. However, when neonatal animals are administered drugs, the combined effect of slow hepatic microsomal metabolic reactions (oxidation and glucuronide conjugation) and inefficient renal excretion mechanisms can decrease considerably the elimination oflipid-soluble drugs and their metabolites. The urinary pH in neonatal animals of all species is acidic in reaction; this would favour renal tubular reabsorption of drugs that are weak organic acids. Neonates of the herbivorous species over 2 days of age appear to have well-developed glomerular filtration and may excrete polar molecules quite efficiently by this renal mechanism. Overall, renal function appears to mature within the first 1 to 2 weeks after birth in calves, lambs, kids (Friis 1983)
foals and piglets (Short 1983). It appears to take longer (at least 4 to 6 weeks) in puppies.
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Correspondence and reprints: Professor J. Desmond HaggaI, Irish Equine Centre. Johnstown, Naas, County Kildare, Ireland.