Ketamine kinetics: decerebrate vs. intact eatsB
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by Depository Services Program on 12/10/14 For personal use only.
JAMESE. H E A V N E RAND DUANE C . BLOEDOW Received Noverl~ber14, 1978
HEAVNER, J. E., and BLOEDOW,D. C. 1979. Ketarnine kinetics: decerebrate vs. intact cats. Can. J. Physiol. Pharrnacol. 57, 878-881. Pharmacokinetic parameters of a ketamine (10 mg/kg, iv) IsoHus in decerebrate and intact cats uiere comparect. A two-con~partrnentopen model best described the data in both groups. The apparent vol~nrneof distribution of the peripheral compartment, the apparent volunle of distribution of the drug in the body, and the half-life of the postdistributive phase were significaiatly less ( p < 0.05) in the decerebrate animals. These results emphasiee the importance of correlating behavior and neuronal activity with plasma or blood concentrations of drug in animals rather than assuming that, for a given drug dose, blood (and thus tissue) levels of the agent will be similar regardless of how the animal is prepared for stbady.
Introduction Relatingdrug-induced changes in ilerlronal activity observed in the acutely prepared animal to behavioral changes induced by the agent in the behavitlg animal is a challenge for the neoroscicntist. is best by URillg prepared animals where behavior and neuronal activity can be ra~easuredstimu%taneously( e . g de Jong and-Heavner 197 i ) . Unfortunately, this optimal sitiation is not always compatible with technical Eirnitations. In s i s h cases, neuronal data obtained from the paralyzed aninsal preparation freqraently are correlated with preexisting knowledge of behavioral changes normally caused by the same dose of drug (e.g. Dbnggan et al. 1977). Another standard for connparison is to pair whole blood or plasma concentration of drug with behavior and with neursnal activity (e.g. Zorychta and Capek 19781. This apprtrach is becornjng more cornmon but generally is not thc rule, in part because facilities for measuring drug cc>ncentration are not always readily available, and in part because the value of such comparison is not gernerally appreciated. The basis of this iinvestigatisn was the hypothesis that thc relationship of drug in thc bloodstream to time aftcr drug administratiorl might vary depending on how the anirrlal is prepared for study. We reasoned, for exaanple, that deeerebratio~lcould reduce the volume of distribution sf a drug which readily crosses the blood-brain barrier. As a result, higher blood levels of the drug would be expected in decerebrate animals as cornpared with levels in animals whose nervous system is intact. Our report describes in phurrnacokinetic terms the changes in plasma concentration of ketamine. a dissociative general anes'Finan~iallysupported by NIH grant G M 1599 1.
thetie, following intravenous injection of a bolus of this agent into decerebmtc and intact Cats. C'ats Were chosen for study because the Zmimal species is Cool"only used as a model to investigate the mode of action of neuroactive substances including ketaminc ( e . ~Mori . et al. 197 1; Kitahata Ct al. 19731.
Methods a,zi,nolP r F p a r ~ t i o n Ten adult male cats weighing 3.20-5.75 kg (4.17 on average) were surgically prepared while anesthetized with halothane. 1n five cats (decerebrate group), polyethylene catheters were placed in a jugular vein (for fluid replacement and drug injection), a carotid artery (for blood pressure monitoring and blood sampling), and in the uriniary bladder (for monitoring urine output). The remaining jugular vein and carotid artery were ligated and the trachea was cannulated through an rtrtificial window for initiation of ~nechanicalkentilation. The cat was them paralyzed vdith gallamine (10 mg) and decerebrated at midcollickllar level. Anesthetic gas delivery evas terminated and physiologic parameters (end-tidal CO,, blood gases, blood pressure, fluid balance, and body temperature) carefully monitored and maintained at normal Ievels. Additional surgical pl-eparation consisted s f high cervical and lumbssacral spinal cord exposure for electropl~ysiologicstudy. The remaining five cats (intact group) were prepared by inserting a polyethylene catheter into a fct~aoralartery. The catheter was tunneled under the skin and externaliaecl on the k~ackin the midlu~nakarregion. T o protect the catheter, cats were placed in stockinette that extended from the neck to the tail and conVnined appropriate holes f o r the limbs. The animals were placed in canvas restraining bags and halothane administration was terminated. One hour later, a 23-gauge needle (Butterfly@ inf~lsionset, Abbott Laboratories) was inscreed percutaneously into a cephalic vein for ketamine injection. ( B ) Kefami~lePrljecriort I, both of cats, olg ketamine hydrochloride per kilogram was rapidly injected intravellously 1 h c)r more after inhalation anesthetic administratioas had cea5ed. All cats were w~adntaincdin the prone position throughout the
0008-4212/79,/080878-04$01.00/0
:Q 1979 National Research Council of Canada/Conseil national de recherches du Canada
879
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by Depository Services Program on 12/10/14 For personal use only.
HEAVNER AND BLOEBOW
PEWlPHERAh
COMPARTMENT
COMPARTMENT
FI~;.I . Schematic representation of the two-compartnlent open model. B represents intravenous bolus dose of ketarnine; C is concentration of ketamine in p~asrnn: C', and V,, are the volumes of distribution of the central and peripheral compartnaents, respectively; h'u and are apparent first-order inter~omp;~rtmcntaldistributioll l-ate constants; K,,, is the apparent first-order elimination rate constant.
studies. A1 terial blood samples were collected ila Bleparinized syringes at 1 , 2.5, 5 , 7.5, 10. 15, 20, 30, 45, and hOmin following injection. An additional arterial blood sample was obtained from the intact cats at 90 nain following injection, Plasma was collected and stored fluzcn until assayed for ketamine base using a gas chsomatographic tecllnique (Ghang and Glaako 1972).
( C ) Kinetic Analysis Plasma concentration data for each animal were fitted to the biexponential e q u a t i ~ n :
where C is the plasma concentration of ketamine base at time t , and A , a , B, and p are conqtants. The fitting was accomplished using the NONLIN nonliilear least-squares program (Metzler et al. 1974). Each plasma concentration datum was weighted with its squared reciprocal. The constants of Eq. 1 derived for each animal and appropriate equations (Gikaldi and Perrier 1975) were rased to calculate pharmacokinetic parameters for the two-compartment open moclel shown in Fig. 1.
Results Average systolic bloed pressure in the decerebrate
animals prior to ketamine injection was 100 torr ( 1 torr = 133.322 Pa). Following ketanline injection, there was a. brief transient fall in pressure, reaching 73 % of control level at 0.5 min and returning to control by 2.5 atlin. Table 1 shows the measured level of kctarnine in the blood of the cats. Using these valucs, estimates for A , a, B, and /3 were determined as described in Methods. These constants for each animal wrere averaged within each group and used lo generate curves indicating the change in ketanline pIasrna co~lcentration with time following intravenous boliis dosing to decerebrate and intact cats (Fig. 2 ) . Based on 95% and confidence limits for these constants ( A , a , P ) and correlation coefficients as estimates of the fit of thc curve to the data, it was determined that a two-cenapartlnei~tope11 model best described the data in all cats. Kctanline plasma concentrations at I min were 16.02 and 16.50 pg/maE in two decerebrate ~ a t x o l n p a r e dwith a range of 9.22 to 12.50 ~ g / r n ~ at B nlin in the remaining three decerebrate cats. These data would indicate that a three-compartment open model may better fit the data for sclected decerebrate cats; however, technical limitrations restrict the collection of enough blood samples in the time span of 0 to 2 rnin to achieve a statistically valid fit of an initial csmpartmcnt from which ketanaine is rapidly redistributed. The curves of Fig. 2 indicate an initial, rapid decline in ketaramine plasma levels in both the decerebrate and intact animals. This rapid decline is refcrred to as the distributive or a phase and represents the distributio~nof ketarniile from the cemtral to the peripheral compartment. When distribution is complete, the ketamine plasma levels in both groups decline at lower rates. This slower decline is rcferrcd to as the postdistributive or /3 phase duri11g which
TABLE 1. Ketamine arterial blood levels in intact and decerebrate cats after intravenous bolus adminiqtration of 10 mg ketamine HClikg
Ketamine Bevel, pg/n~l, Time after injection, min
Intact cats
Decerebratc cats
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CAN. J, PHYSIBE. PHARM.4GBL. VOE. 57. I979
Values for celected pharmacokinetic pararlneters are stamanarized in Table 2. The apparent volunle c ~ f the central compartment (V.',), an initial dilution volume based on plasma sampling, is less in the decerebrate group. The apparent vol~imeof distribution of the peripheral compartment (V,,) is also less in the decerebrate group, this difTerencc being statistically significallt (1;" < 0.05). The half-lives of the distributive (t.ja) and postdistributive ( t $ , biologic half-life) phases are less in the decerebrate group. The difference is statistically sigraificrtnt ( p < 0.05) for the half-life of the postdistributive phase. The plasma clearance of ketarnine, a paranneter which describes the efficiency of drug elinnination, is siiasilar for both groups of animals.
- - - Decerebrate
lntact
The two-conapartment open n~odelfor drug disposition predicts that the half-life of the postdistributivc phase (biologic half-life) is a function of distribution volume arsd clearance according to the fc~llowing equation : [2]
rho
=
0.693 VB plasma clearance
where VII is the apparent vslun~eof distribution of the drug in the body, i.e. V,, V,,in the postdistributive period. This relationslnip indicates that the shorter biologic half-life for ketarains in the decerebrats animals is a result of a decrease in distribartior~ volume, sincc the plasma clearance sf ketanaminc remains re1atively unchanged f allowing decerebration. A sinailar argument applies also for the volume of distribution of the central compartment, rt parameter which largely reflects i~mitialdilution and naixing of ketamine within the blood. Although the volumcs of distxib~~tion of the central coaaapartrne~~ts are not statisitically different when the decerebrate and intact groups are compared, the central compartment volumc sf distribution appears to decrease after dccerebration. In addition, as stated previously, the assayed ketamine plasma conceratratiom at 1 ~ n i nin two decerebrate animals appearcel higher than would be predicted by the two-comipartment n-aodel; t h ~ ~the s,
+
FIG. 2. Arterial ketamine plasma concentr ation-ei~ns:~tion-time Gnrves following irllrave~norlsbolrss administration of 10 rr1g ke tanair~e hydrochloride per kilogram to deserebrate and intact cats. Cornpuler-determined estinaates for A , a, W , rand p (Eq. 1 ) for each animal were average~tand rased to generate these curves. HOWVP~CII the CUPVCS represent the raw data is indicated by the standard deviations shown in 'Table 2.
tinle kctarnine is irreversibly eliminated (by mctabolism or excretion) from the central compartment. Figure 2 sIiows that this phase proceeds more rapidly in the deccrcbrate animals.
--
T A B I 2. , ~ PIaarmacokinetic parameters in decerebrate and intact cats following intravenous bolus adnrinistration of ketamirle hydrochloride (means i- SD) pa.-
Piasrnt-1 VC I>/kg 9
Decerebrat e Intact
0.7620.19 0.93 1 0 . 2 1
1; ,
k!kg 0.94~0.22" 1.36xtB.24
I[B , L!kg 1.97~0.40* 2.73 i-0.46
63 7,
mln 3.6L1.8 5.011.8
ri(%
clearance, mH, nlin-1 kg-'
38.6511.9"
3'9.1 5 9 . 5 33.0110.9
n ~ ~ n 61 - 4 2 18.1
*Indic:~tes statistically sigr~ificantdifference (p i 0.05) betwecn she decrrebrate n ~ i dintact groups using Student's I test.
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HEAVNEW AND BLBEDOW
mean volume sf distribution of the central compartment in the dccerebrate cats rnay have been overestimated. A comparison of the volumes of distribution of the peripheral compartments between thc two groups indicates that a difference in ketarnine distribaltion into the peripheral or tissue compartment results from decerebration. However, because the calculated volumes of distribution do not necessarily represent specific organ or tissue groups, no statement can bc made as to whether the transected portion of the tissue lies within the central OH. peripheral compartment. FVllen adjusted for dose, the plasnna levels of ketamine i~athe intact cat reported here are substantially lower than those reported in a previous study (Baggot and Blake 19'76). As a result, our vrt%ucsfor distribution volun~esand clearance are substantially higher. Because our values for distribution ( t: a ) and elimnination ( t i p ) half-lives are in agreement with those reported previously, the difference between the two studies appears to be a difference of assay procedure or dosing. Our assay, based on a published procedure (Cbang and Glazko 19'721, was validated by obtaining nearly identical data points on duplicate standard curves determined on separate occasions. Our ketaanine doses were drawn from the sanae lot of Ketalafl (Parkc, Davis and Company). The results of this study show that decerekratioim (and possibly the associated surgery ) significantly reduces distribution volume of ketarnine in cats. emphasizir~gthe importance of correlating behavior and neuronal activity with plasma or blood concentrations of the drug in the animal as prepared for study. Presumably, the concentration of drug at the site of action is related in soll-ae manner to the concer-atration of the drug in the plasma. With a drug such as ketamine which has a relatively short half-life in the body, the concentration of the drug at the site of action may change rapidly. Thus, optimal experimental design may dictate the measurement of behavior and nealroi~alactivitj, at steady-state levels sf drug in the b~xtyrather than following intravenous bolus injection. This requires administering the drug by infusion at a constant rate calculated to aclaieve a desired plasma concentration of the drug (Gihaldi and Perrier % 975). To achieve true steady-state concealtra-
88 1
tions, the drug should be infused for about six halfBives ( t i P ) or about 4 h and 6 h for the decerebrate and intact cats, respectively, as predicted by the data in this study. Shorter infusion periods arc possible, with sonre theoretical difference from true steadystate plasma levels, if a bolus intravenous injection of the drug is rapidly administered at the start of the infusioil. Administration sf drug by other routes, such as by ia-rtramuscularor intraperitoneal injection, introduces an absorption step wlaich, when compared with intravenous administration. usually decreases and prolongs pilasnla levels in addition to increasing the difficulty in predicting plasma levels of the drug. Hla addition, dose repetition during the staady produces oscillation in drug levels which adds difficulty in interpretation of bellavior and netaronal activity as correlated with plasma Bevels of the drug. Irrespective of the method of administering the drug, it should be emphasized that phararlacokirlctic data in nonprepared (normal) animals should be applicd cautioa~sly,if at all, to animals prepared for study using methods like1y to drastically alter physiologic and (or) anatomic parameters in the animal. BAGGOT,J. D., and BLAME, J. W. 1976. Disposition kinetics of ketamine in the domestic cat. Arch. Int. IdRarmacody~a. Ther. 220, 1 15-124. CHANG, T., and GH~AZKO, A. J. 197%. A gas chromatographic assay for ketamine in human plasma. Anesthesiology, 36, 401-404. DUGGAN, A. W., HALL,J. G., HEADLEY, 1'. M., and GWERSMITH, B. T. 1977. The effect of naloxone on the excitation of dorsal horn neurones of the cat by noxious and nonnoxious cutaneous stimuli. Brain Res. 138, 185-189. G ~ n r A L n r ,M., and PERKIER, D. 1975. Phar~macskianetics.h?farcel Dekker, Inc., New York. JONG,R. H., DE, and HEAVNER, J. E. 1971. Correlation of the ethane clectroetncephalogram with motor activity in cats. Anesthesiology, 35, 474-481. KITAHATA, L. M., TAUB,A., and YOSAKA,Y. 1973. Larninaspecific suppression of dorsal horn unit activity by ketarnine hydrc~chloride.Anesthesiology, 38,4-11. METZLER, C . M., E:LI;IIHNG, C. E., and MCFRJEN,A. J. 1974. A package of computer programs for pharmacokinetic n~odeling.Biometries, 30, 562 (abstract). Mor
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by Depository Services Program on 12/10/14 For personal use only.
JAMESE. H E A V N E RAND DUANE C . BLOEDOW Received Noverl~ber14, 1978
HEAVNER, J. E., and BLOEDOW,D. C. 1979. Ketarnine kinetics: decerebrate vs. intact cats. Can. J. Physiol. Pharrnacol. 57, 878-881. Pharmacokinetic parameters of a ketamine (10 mg/kg, iv) IsoHus in decerebrate and intact cats uiere comparect. A two-con~partrnentopen model best described the data in both groups. The apparent vol~nrneof distribution of the peripheral compartment, the apparent volunle of distribution of the drug in the body, and the half-life of the postdistributive phase were significaiatly less ( p < 0.05) in the decerebrate animals. These results emphasiee the importance of correlating behavior and neuronal activity with plasma or blood concentrations of drug in animals rather than assuming that, for a given drug dose, blood (and thus tissue) levels of the agent will be similar regardless of how the animal is prepared for stbady.
Introduction Relatingdrug-induced changes in ilerlronal activity observed in the acutely prepared animal to behavioral changes induced by the agent in the behavitlg animal is a challenge for the neoroscicntist. is best by URillg prepared animals where behavior and neuronal activity can be ra~easuredstimu%taneously( e . g de Jong and-Heavner 197 i ) . Unfortunately, this optimal sitiation is not always compatible with technical Eirnitations. In s i s h cases, neuronal data obtained from the paralyzed aninsal preparation freqraently are correlated with preexisting knowledge of behavioral changes normally caused by the same dose of drug (e.g. Dbnggan et al. 1977). Another standard for connparison is to pair whole blood or plasma concentration of drug with behavior and with neursnal activity (e.g. Zorychta and Capek 19781. This apprtrach is becornjng more cornmon but generally is not thc rule, in part because facilities for measuring drug cc>ncentration are not always readily available, and in part because the value of such comparison is not gernerally appreciated. The basis of this iinvestigatisn was the hypothesis that thc relationship of drug in thc bloodstream to time aftcr drug administratiorl might vary depending on how the anirrlal is prepared for study. We reasoned, for exaanple, that deeerebratio~lcould reduce the volume of distribution sf a drug which readily crosses the blood-brain barrier. As a result, higher blood levels of the drug would be expected in decerebrate animals as cornpared with levels in animals whose nervous system is intact. Our report describes in phurrnacokinetic terms the changes in plasma concentration of ketamine. a dissociative general anes'Finan~iallysupported by NIH grant G M 1599 1.
thetie, following intravenous injection of a bolus of this agent into decerebmtc and intact Cats. C'ats Were chosen for study because the Zmimal species is Cool"only used as a model to investigate the mode of action of neuroactive substances including ketaminc ( e . ~Mori . et al. 197 1; Kitahata Ct al. 19731.
Methods a,zi,nolP r F p a r ~ t i o n Ten adult male cats weighing 3.20-5.75 kg (4.17 on average) were surgically prepared while anesthetized with halothane. 1n five cats (decerebrate group), polyethylene catheters were placed in a jugular vein (for fluid replacement and drug injection), a carotid artery (for blood pressure monitoring and blood sampling), and in the uriniary bladder (for monitoring urine output). The remaining jugular vein and carotid artery were ligated and the trachea was cannulated through an rtrtificial window for initiation of ~nechanicalkentilation. The cat was them paralyzed vdith gallamine (10 mg) and decerebrated at midcollickllar level. Anesthetic gas delivery evas terminated and physiologic parameters (end-tidal CO,, blood gases, blood pressure, fluid balance, and body temperature) carefully monitored and maintained at normal Ievels. Additional surgical pl-eparation consisted s f high cervical and lumbssacral spinal cord exposure for electropl~ysiologicstudy. The remaining five cats (intact group) were prepared by inserting a polyethylene catheter into a fct~aoralartery. The catheter was tunneled under the skin and externaliaecl on the k~ackin the midlu~nakarregion. T o protect the catheter, cats were placed in stockinette that extended from the neck to the tail and conVnined appropriate holes f o r the limbs. The animals were placed in canvas restraining bags and halothane administration was terminated. One hour later, a 23-gauge needle (Butterfly@ inf~lsionset, Abbott Laboratories) was inscreed percutaneously into a cephalic vein for ketamine injection. ( B ) Kefami~lePrljecriort I, both of cats, olg ketamine hydrochloride per kilogram was rapidly injected intravellously 1 h c)r more after inhalation anesthetic administratioas had cea5ed. All cats were w~adntaincdin the prone position throughout the
0008-4212/79,/080878-04$01.00/0
:Q 1979 National Research Council of Canada/Conseil national de recherches du Canada
879
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by Depository Services Program on 12/10/14 For personal use only.
HEAVNER AND BLOEBOW
PEWlPHERAh
COMPARTMENT
COMPARTMENT
FI~;.I . Schematic representation of the two-compartnlent open model. B represents intravenous bolus dose of ketarnine; C is concentration of ketamine in p~asrnn: C', and V,, are the volumes of distribution of the central and peripheral compartnaents, respectively; h'u and are apparent first-order inter~omp;~rtmcntaldistributioll l-ate constants; K,,, is the apparent first-order elimination rate constant.
studies. A1 terial blood samples were collected ila Bleparinized syringes at 1 , 2.5, 5 , 7.5, 10. 15, 20, 30, 45, and hOmin following injection. An additional arterial blood sample was obtained from the intact cats at 90 nain following injection, Plasma was collected and stored fluzcn until assayed for ketamine base using a gas chsomatographic tecllnique (Ghang and Glaako 1972).
( C ) Kinetic Analysis Plasma concentration data for each animal were fitted to the biexponential e q u a t i ~ n :
where C is the plasma concentration of ketamine base at time t , and A , a , B, and p are conqtants. The fitting was accomplished using the NONLIN nonliilear least-squares program (Metzler et al. 1974). Each plasma concentration datum was weighted with its squared reciprocal. The constants of Eq. 1 derived for each animal and appropriate equations (Gikaldi and Perrier 1975) were rased to calculate pharmacokinetic parameters for the two-compartment open moclel shown in Fig. 1.
Results Average systolic bloed pressure in the decerebrate
animals prior to ketamine injection was 100 torr ( 1 torr = 133.322 Pa). Following ketanline injection, there was a. brief transient fall in pressure, reaching 73 % of control level at 0.5 min and returning to control by 2.5 atlin. Table 1 shows the measured level of kctarnine in the blood of the cats. Using these valucs, estimates for A , a, B, and /3 were determined as described in Methods. These constants for each animal wrere averaged within each group and used lo generate curves indicating the change in ketanline pIasrna co~lcentration with time following intravenous boliis dosing to decerebrate and intact cats (Fig. 2 ) . Based on 95% and confidence limits for these constants ( A , a , P ) and correlation coefficients as estimates of the fit of thc curve to the data, it was determined that a two-cenapartlnei~tope11 model best described the data in all cats. Kctanline plasma concentrations at I min were 16.02 and 16.50 pg/maE in two decerebrate ~ a t x o l n p a r e dwith a range of 9.22 to 12.50 ~ g / r n ~ at B nlin in the remaining three decerebrate cats. These data would indicate that a three-compartment open model may better fit the data for sclected decerebrate cats; however, technical limitrations restrict the collection of enough blood samples in the time span of 0 to 2 rnin to achieve a statistically valid fit of an initial csmpartmcnt from which ketanaine is rapidly redistributed. The curves of Fig. 2 indicate an initial, rapid decline in ketaramine plasma levels in both the decerebrate and intact animals. This rapid decline is refcrred to as the distributive or a phase and represents the distributio~nof ketarniile from the cemtral to the peripheral compartment. When distribution is complete, the ketamine plasma levels in both groups decline at lower rates. This slower decline is rcferrcd to as the postdistributive or /3 phase duri11g which
TABLE 1. Ketamine arterial blood levels in intact and decerebrate cats after intravenous bolus adminiqtration of 10 mg ketamine HClikg
Ketamine Bevel, pg/n~l, Time after injection, min
Intact cats
Decerebratc cats
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CAN. J, PHYSIBE. PHARM.4GBL. VOE. 57. I979
Values for celected pharmacokinetic pararlneters are stamanarized in Table 2. The apparent volunle c ~ f the central compartment (V.',), an initial dilution volume based on plasma sampling, is less in the decerebrate group. The apparent vol~imeof distribution of the peripheral compartment (V,,) is also less in the decerebrate group, this difTerencc being statistically significallt (1;" < 0.05). The half-lives of the distributive (t.ja) and postdistributive ( t $ , biologic half-life) phases are less in the decerebrate group. The difference is statistically sigraificrtnt ( p < 0.05) for the half-life of the postdistributive phase. The plasma clearance of ketarnine, a paranneter which describes the efficiency of drug elinnination, is siiasilar for both groups of animals.
- - - Decerebrate
lntact
The two-conapartment open n~odelfor drug disposition predicts that the half-life of the postdistributivc phase (biologic half-life) is a function of distribution volume arsd clearance according to the fc~llowing equation : [2]
rho
=
0.693 VB plasma clearance
where VII is the apparent vslun~eof distribution of the drug in the body, i.e. V,, V,,in the postdistributive period. This relationslnip indicates that the shorter biologic half-life for ketarains in the decerebrats animals is a result of a decrease in distribartior~ volume, sincc the plasma clearance sf ketanaminc remains re1atively unchanged f allowing decerebration. A sinailar argument applies also for the volume of distribution of the central compartment, rt parameter which largely reflects i~mitialdilution and naixing of ketamine within the blood. Although the volumcs of distxib~~tion of the central coaaapartrne~~ts are not statisitically different when the decerebrate and intact groups are compared, the central compartment volumc sf distribution appears to decrease after dccerebration. In addition, as stated previously, the assayed ketamine plasma conceratratiom at 1 ~ n i nin two decerebrate animals appearcel higher than would be predicted by the two-comipartment n-aodel; t h ~ ~the s,
+
FIG. 2. Arterial ketamine plasma concentr ation-ei~ns:~tion-time Gnrves following irllrave~norlsbolrss administration of 10 rr1g ke tanair~e hydrochloride per kilogram to deserebrate and intact cats. Cornpuler-determined estinaates for A , a, W , rand p (Eq. 1 ) for each animal were average~tand rased to generate these curves. HOWVP~CII the CUPVCS represent the raw data is indicated by the standard deviations shown in 'Table 2.
tinle kctarnine is irreversibly eliminated (by mctabolism or excretion) from the central compartment. Figure 2 sIiows that this phase proceeds more rapidly in the deccrcbrate animals.
--
T A B I 2. , ~ PIaarmacokinetic parameters in decerebrate and intact cats following intravenous bolus adnrinistration of ketamirle hydrochloride (means i- SD) pa.-
Piasrnt-1 VC I>/kg 9
Decerebrat e Intact
0.7620.19 0.93 1 0 . 2 1
1; ,
k!kg 0.94~0.22" 1.36xtB.24
I[B , L!kg 1.97~0.40* 2.73 i-0.46
63 7,
mln 3.6L1.8 5.011.8
ri(%
clearance, mH, nlin-1 kg-'
38.6511.9"
3'9.1 5 9 . 5 33.0110.9
n ~ ~ n 61 - 4 2 18.1
*Indic:~tes statistically sigr~ificantdifference (p i 0.05) betwecn she decrrebrate n ~ i dintact groups using Student's I test.
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HEAVNEW AND BLBEDOW
mean volume sf distribution of the central compartment in the dccerebrate cats rnay have been overestimated. A comparison of the volumes of distribution of the peripheral compartments between thc two groups indicates that a difference in ketarnine distribaltion into the peripheral or tissue compartment results from decerebration. However, because the calculated volumes of distribution do not necessarily represent specific organ or tissue groups, no statement can bc made as to whether the transected portion of the tissue lies within the central OH. peripheral compartment. FVllen adjusted for dose, the plasnna levels of ketamine i~athe intact cat reported here are substantially lower than those reported in a previous study (Baggot and Blake 19'76). As a result, our vrt%ucsfor distribution volun~esand clearance are substantially higher. Because our values for distribution ( t: a ) and elimnination ( t i p ) half-lives are in agreement with those reported previously, the difference between the two studies appears to be a difference of assay procedure or dosing. Our assay, based on a published procedure (Cbang and Glazko 19'721, was validated by obtaining nearly identical data points on duplicate standard curves determined on separate occasions. Our ketaanine doses were drawn from the sanae lot of Ketalafl (Parkc, Davis and Company). The results of this study show that decerekratioim (and possibly the associated surgery ) significantly reduces distribution volume of ketarnine in cats. emphasizir~gthe importance of correlating behavior and neuronal activity with plasma or blood concentrations of the drug in the animal as prepared for study. Presumably, the concentration of drug at the site of action is related in soll-ae manner to the concer-atration of the drug in the plasma. With a drug such as ketamine which has a relatively short half-life in the body, the concentration of the drug at the site of action may change rapidly. Thus, optimal experimental design may dictate the measurement of behavior and nealroi~alactivitj, at steady-state levels sf drug in the b~xtyrather than following intravenous bolus injection. This requires administering the drug by infusion at a constant rate calculated to aclaieve a desired plasma concentration of the drug (Gihaldi and Perrier % 975). To achieve true steady-state concealtra-
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tions, the drug should be infused for about six halfBives ( t i P ) or about 4 h and 6 h for the decerebrate and intact cats, respectively, as predicted by the data in this study. Shorter infusion periods arc possible, with sonre theoretical difference from true steadystate plasma levels, if a bolus intravenous injection of the drug is rapidly administered at the start of the infusioil. Administration sf drug by other routes, such as by ia-rtramuscularor intraperitoneal injection, introduces an absorption step wlaich, when compared with intravenous administration. usually decreases and prolongs pilasnla levels in addition to increasing the difficulty in predicting plasma levels of the drug. Hla addition, dose repetition during the staady produces oscillation in drug levels which adds difficulty in interpretation of bellavior and netaronal activity as correlated with plasma Bevels of the drug. Irrespective of the method of administering the drug, it should be emphasized that phararlacokirlctic data in nonprepared (normal) animals should be applicd cautioa~sly,if at all, to animals prepared for study using methods like1y to drastically alter physiologic and (or) anatomic parameters in the animal. BAGGOT,J. D., and BLAME, J. W. 1976. Disposition kinetics of ketamine in the domestic cat. Arch. Int. IdRarmacody~a. Ther. 220, 1 15-124. CHANG, T., and GH~AZKO, A. J. 197%. A gas chromatographic assay for ketamine in human plasma. Anesthesiology, 36, 401-404. DUGGAN, A. W., HALL,J. G., HEADLEY, 1'. M., and GWERSMITH, B. T. 1977. The effect of naloxone on the excitation of dorsal horn neurones of the cat by noxious and nonnoxious cutaneous stimuli. Brain Res. 138, 185-189. G ~ n r A L n r ,M., and PERKIER, D. 1975. Phar~macskianetics.h?farcel Dekker, Inc., New York. JONG,R. H., DE, and HEAVNER, J. E. 1971. Correlation of the ethane clectroetncephalogram with motor activity in cats. Anesthesiology, 35, 474-481. KITAHATA, L. M., TAUB,A., and YOSAKA,Y. 1973. Larninaspecific suppression of dorsal horn unit activity by ketarnine hydrc~chloride.Anesthesiology, 38,4-11. METZLER, C . M., E:LI;IIHNG, C. E., and MCFRJEN,A. J. 1974. A package of computer programs for pharmacokinetic n~odeling.Biometries, 30, 562 (abstract). Mor
