Acta Clinica Belgica International Journal of Clinical and Laboratory Medicine
ISSN: 1784-3286 (Print) 2295-3337 (Online) Journal homepage: http://www.tandfonline.com/loi/yacb20
Toxicokinetics in Clinical Toxicology A. Jaeger, Ph. Sauder, Kopferschmitt & M. Dahlet To cite this article: A. Jaeger, Ph. Sauder, Kopferschmitt & M. Dahlet (1990) Toxicokinetics in Clinical Toxicology, Acta Clinica Belgica, 45:sup13, 1-12, DOI: 10.1080/17843286.1990.11718122 To link to this article: http://dx.doi.org/10.1080/17843286.1990.11718122
Published online: 16 May 2016.
Submit your article to this journal
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=yacb20 Download by: [University of Tasmania]
Date: 09 April 2017, At: 15:17
1
TOXICOKINETICS IN CLINICAL TOXICOLOGY A. Jaeger, Ph. Sauder, Kopfe rschmitt, M. Dahl et''
SUM MARY Toxicokinetics is an essential step in clinical toxicology. The methodology is based on the same parameters which are used in pharmacokinetics. However, the interpretation and the aims are different. For each toxico n, the interpretation of kin e tic data needs to take account of the spontaneous toxicokinetics, the factors of varia tion, the relationship kinetic d ata and symptoms, the severity and prognosis criteria. The evaluatio n of treatment has to take account of the global kinetic action of the toxicon during the intoxicatio n and the effects on the symptomatology. The mechanism of toxicity, is an essential item in the interpretation of toxicokine tic data. By the exact knowledge of toxicokinetics, it is possible to determine for each toxicon, the relevant parameters which will be of use in clinical practice.
INTRODUCTION In clinical toxicology, kinetic studies should help answer the following questions : Is the symptomatology of the patient correlated with kinetic data and especially with the serum or blood concentrations? Is the kinetic profile of the patient similar or different from the spontaneous toxicokinetic ? • Service de Reanimation Medicale et Cen tre An ti· Poisons - Pavilion Pasteur - l place de l'H6pital - 67091 Stra bourg Cedex - France
Which patient will benefit from specific treatments such as enhanced drug elimination or antidotes ? Which kinetic parameter will be of use to identify this patient ? A rational approach to the toxicokinetics requires, in each case, the assessment of the global kinetic of the toxicon during the intoxication. The interpretation of analytical data needs knowledge of, for each toxicon, the spontaneous toxicokinetic, its variations, the relations between symptomatology and kinetic data, the prognostic criteria. Moreover the interpretation has to take into account the mechanism of toxicity. METHODOLOGY OF TOXICOKINETI CS The methodology includes biological sample collection, specific analytical methods and calcul ations of kinetic parameters. Sample collection and timing need special attention and have to be adapted to each toxic. For a complete toxicokinetic study it is necessary to perform analysis in various biological fluids : blood or serum urine gastric lavage fluid, dialysate fluid, blood from the inlet and outlet sides of the dialyser or the he moperfusion column. Analysis of other biological samples such as feces or cerebrospinal fluid may sometimes be interesting.
2 The diffe rent toxicokinetic parameters are calculated according to the equations shown in table I (1, 2).
Plasma kinetics. Most drugs or toxicons are eliminated from the body according to a first order kinetic (equation 1). The plasma half life (equation 2) is more conveniently applied to the clinical use than the elimination rate. If the plasma concentration cuive shows several slopes, it denotes a multicompartment kinesis which may be due to a distribution phase or to several elimination rates. An increase of the concentrations at the initial phase of the intoxication is mostly due to a continuation of the gastrointestinal absorption of the toxicon. Clearances. In ordre to estim ate th e re pective importance of the differe nt excretory routes it is essenti al to compare renal and hemodialysi or hemoperfu ion clearances with th e total body clearance (eq uation 3-4·6). If a toxicon i eliminated by renal route and hepatic metabolism, the he patic or metabolic clearance can be calculated as hown in equation 5. For the calculation of the hemody ly i or hemope rfu sion clearances it is also essential to u e eith er the erum or the blo d flow rate through the device according to the concentration which have been measured in the serum or in the whole blood. If the drug is analy ed in se rum , calculations u ing th e blo d flow rate may lead to an overe tim ation of the cleara nce and of the effici ency of th e method. Amounts eliminated. The amounts eliminated by the different routes or by speci fic treatme nt are calculated according to the equations 7-8- 9. The e amount are often compared with the amount ingested. ff a part of the toxicon ha been eliminated by gastric lavage, a compari on with th e amount potentially absorbed (equation I0) i more accurate. However in mo t ca es the exact amount ingested is not exactly known, and a part of the toxicon may have been eliminated by vomiting or has bee n
TOXICOKJNETICS IN CLINICAL TOXICOLOGY
metabolized by the liver during the first passage. Thus, in these cases it is interesting to calculate the amount bioavailable at a given time of the intoxication (equation 11) or to estimate retrospectively the total amount bioavailable namely the total amount eliminated during the intoxication (equation 12).
RESULTS AND CLINI CAL APPLI ATIONS In intoxicated patients, the kinetics of a drug may be quite different from the kinetic afte r therapeutic do es (1, 3). Indeed, the amount of drug ingested and symptoms such as a circulatory failure, a hypoxemia may strongly influence spontaneous kinetic · and especially the intestinal absorption, the renal excretion and the hepatic metabolism. Thus the study of the spontaneous toxicokinetic is an essential step for the determination of the kinetic parameters which will later be used as references for the studies of the variations, factors, of the prognostic criteria and of treatment efficiency. The following examples show several applications of toxicokinetics in clinical toxicology. 1. SPONTANEOUS TOXICOKJNETICS
Phenobarbital intoxication. Figure 1 shows an example of spontaneous kinesis in a 46-year-old man with an overdose of 6 g of phenobarbital. Plasma concentrations decreased only after the 32nd hour post ingestion with an apparent half life of 39.5 hours. The estimated half life of aborption was 5.9 hours. Twenty-six per cent of the drug ,absorbed was eliminated in urine and 74 per cent by hepatic metabolism. In this case, the total amount eliminated by the different routes (5,75 g) was very close to the as urned amount ingested (6 g).
Quinine intoxication. A 32-year-old man treated for acute malaria was admitted after an accidental overdose of 5 g intravenous
3
TOXJCOKJNETICS IN CLINICAL TOXICOLOGY
quinine (figure 2). The kinetic data (plasma half life, volume of distribution, clearances) were similar to the parmacokinetic parameters. Therefore, the quinine kinetic seems not to be dose related.
2. KJNETIC VA RIATIONS The sponta neous kinetic of a toxicon may be changed by num erous factors : dose ingested,age, sex, other drugs ingested, symptoms. Zero order kinetics have been reported in theophyllin e a nd sa licylate massive overdoses ( 4). The plasma half life of flunitrazepam increases according to the dose ingested probably because th e gastrointe tinal absorption is increased or because the hepatic metabolism is progressively saturated (5). The plasma half-life of triazolam is also increased when other psychotropic drugs have been ingested (1). In meprobamate overdose, the meprobamate plasma half life is strongly increased and the total, renal and metabolic clearances are ) decreased when barbiturates have also been ingested or when there is a circulatory failure (6). The elimination of theophylline ' is also strongly decreased in patients with congestive heart failure (table 2). In order to enhance the drug elimination in these patients with a circulatory failure, it is as important to correct the shock as to pe rform a hemodialysis or a hemoperfusion.
half life decreased from 7 to.4.5 hours after the administration of oral activa ted charcoa l. Howeve r a fall in plasma concentrations or a decrease of th e plasma half life is not definite evidence of treatment efficiency. In a case of secobarbital overdose (figure 4) the plasma concentration decreased during hemodialysis although no secobarbital was e limin ated by this route. The fall in plasma co nce ntration was due to a stop of the gastrointestin al absorption. The case of theophylline overdose in a 26-year-old man reported in table 3 shows the int erest of a com pl ete kinetic study. The plasma peak conce ntration occured only at the 11th ho ur post ingestion because of the slow absorption of the susta in ed re lease form of th eophylline. Therefore the gastric lavage pe rform ed at 1.5 hour post-ingestion, e limin ated 25.5 per cent of the amount ingested. The hemodialysis re moved 10.9 pe r cent of the potentially absorbed amount. Howeve r the he modia lysi clearance was lowe r th an the total and me tabolic clearances indicating that the major part of theophyllin e was e liminated by hepatic me tabolism. The calculated amount of theophylline e limin ated by hemodialysis was close to the amount measured in dialysate fluid s. This confirms th e accuracy of th e calculation me thod (equ ation 9) using the se rum concentration and th e serum flow rate through the dialyser.
3. EVALUATION OF TREATMENT The evalu ation of th e el imin ation me thods should be based not only on clinical improve me nt, high clea rances values, decrease of pla ma concentrations a nd half life, but also on the amounts of toxicon e liminated by the diffe rent routes (1, 4, 7, 8, ' 9). Sometimes however this methodology is not applied to the type of treatment. For instance the effect of oral activated charcoal can only be estimated by the variations of plasma concentrations, half lives and total clearances (10). In the case of theophylline intoxication reported in figure 3, the plasma
4. BIOAVAILABLE AMOUNTS Calculation of the bioavailable amounts may have several uses. The total amount bioava ilable (ABT) or the amount bioavailable at plasma peak concentration (ABT) may be compared with the amounts ingested (1). Calculation of the amounts bioavailable at given times may also be used for the estimation of the amount of drug metabolized during a treatment with hemodialysis or hemoperfusion (7). A study performed in 13 cases of phenobarbital intoxication showed that the calculated total
4
TOXTCOKJNETICS IN CLINICAL TOXICOLOGY
TABLE 1: CALCULATION OF TOXICOKINETIC PARAMETERS PLASMA KINETIC * Plasma (blood) concentration curve Equation 1:
Cpt
= Cpo (e - K•t)
* Plasma (blood) half life T 112
Log2 Ke
Equation 2 :
=--
CLEARANCES *Total body clearance (CIT) Equation 3:
CIT log 2 x VD x W T112
* Renal clearance (CIR)
Ke x VD x W
Cu x Qu Cp
Equation 4: * Metabolic clearance (CIM) Equation 5 :
* Hemodialysis or hemoperfusion clearance (CIHo) · 6: Cl Ho = __. C;. Cou1) .;.;.;._- ____;, ,;;.;.;Qs . . __ E quatton
cin
AMOUNTS ELI MINATED * In urine (Au) Equation 7 :
Au
=
AM
=
Cu x Vu
*By hepatic metabolism (AM) Equation 8:
Au
X CIM CIR
* By hemodialysis or hemoperfu ion (A 110 ) Equation 9:
CLim x Cin
A Ho
X
AMOUNT POTENTIALLY ABSORBED (AA) Equation 10 : BIOAV AILABLE AMOUNT * Bioavailable amount at time t quation 11:
A 81
= CP, x
AeT
=
* Total available amount Equation 12 :
C4 x Cl
x
VD Au R
W
THO
)
5
TOXICOKINETICS IN CLINICAL TOXICOLOGY
amounts eliminated during the intoxication (ABT) correlated well with the plasma peak concentrations and with the bioavailable amounts calculated with the plasma peak concentration (ABT) (figure 5-6). These results show that in phenobarbital intoxication, the plasma peak concentration is a relevant parameter for the estimation of the amount of bioavailable phenobarbital. INTE RPRETATION The interpretation of kinetic data has also to take into account the mechanism of toxicity (5). For this purpose, three classes of toxicons can be distinguished : the functional toxicons, th e lesional toxicons and the toxicons which may act by both mechani sms. I. FUNCTIONAL TOXJCONS
Barbiturates, mepro ba ma te, be nzodiazepines, cardiotropic drugs, lithium for instance act as function al toxicons. They impair the function of one or several organs and the patients recover without sequelae if no complications have occured during the intoxication. Their toxicity is directly related to the concentration at the targe t or rece ptor and the subsequent evolution is depe ndent on the elimination of the toxicon from these fixation sites. Symptoms occur only when the plasma or blood concentration is higher than a de finite threshold and their seve rity increases according to the concentrations (figure 7). The duration of the symptoms is dependent on the plasma or blood half life and on the elimination of the toxicon. The aim of the treatm ent is to decrease the conce ntration of the toxicon at the targe t organs and to enhance the elimination from the body. For most functional toxicons there is a good relationship between plasma or blood concentrations and symptomatology. However this relationship may be changed by several factors such as active or toxic metabolites, cause of the intoxication, underlying diseases, age. For instance
in amitriptyline overdoses, the underestimation of the active metabolite, nortriptyline, may lead to a gap between cardiac symptoms and plasma concentrations (11 ). For th eophylline, lithium, phenobarbital, th e relationship symptomatology-plasma concentrations is different if the intoxication is acute, chronic or acute upon chronic (12, 13). An underlying cardiac disease is an aggravating factor in poisoning with cardiotoxic drugs. In these patients, cardiotoxicity may appear at lower concentrations than in patients without cardiac dis~ase (14). The effects of treatment can be deducted from the kinetic data. For toxicons with high total clearance and high rate of hepatic metabolism, forced diuresis or extracorporeal elimination methods will be of little use in order to enhance the elimination (1, 4). For many drugs, the amounts eliminated by hepatic metabolism are higher than the amounts removed by hemodialysis or hemoperfusion (1, 7). A comparison of the clearances of 5 barbiturates show that the differences in total clearance values are related to the different rates of hepatic metabolism (table 4). These data indicate that the elimination of phenobarbital only will be significantly increased by forced diuresis, hemodialysis or hemoperfusion. 2. LESIONAL TOXICONS
Paraqu at, amatoxins, colchicine and most heavy metals are typical examples of toxicons which cause organ or cellular damage. Thei r toxicity is dependent on the maximal concentration reached at the target organ. Symptoms do not always improve eve n though the toxicon is eliminated from the target organ or the body because cellular damage has occured before. Severity, prognosis and indications of treatment can only be determinated by the estimation of plasma concentrations and kinetic data in relation to time after ingestion or exposure. The same plasma concentration may be non
6 toxic, toxic or lethal according to the time at which the concentration is measured (figure 8). Paraquat is a typical example of the contribution of toxicokinetic to the . assessment of prognostic criteria (15). Plasma paraquat concentrations related to time since ingestion are a good indication for severity and prognosis. Treatment which enhances the toxicon elimination will only be efficient if they are administered before severe cellular damage has oe
ISSN: 1784-3286 (Print) 2295-3337 (Online) Journal homepage: http://www.tandfonline.com/loi/yacb20
Toxicokinetics in Clinical Toxicology A. Jaeger, Ph. Sauder, Kopferschmitt & M. Dahlet To cite this article: A. Jaeger, Ph. Sauder, Kopferschmitt & M. Dahlet (1990) Toxicokinetics in Clinical Toxicology, Acta Clinica Belgica, 45:sup13, 1-12, DOI: 10.1080/17843286.1990.11718122 To link to this article: http://dx.doi.org/10.1080/17843286.1990.11718122
Published online: 16 May 2016.
Submit your article to this journal
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=yacb20 Download by: [University of Tasmania]
Date: 09 April 2017, At: 15:17
1
TOXICOKINETICS IN CLINICAL TOXICOLOGY A. Jaeger, Ph. Sauder, Kopfe rschmitt, M. Dahl et''
SUM MARY Toxicokinetics is an essential step in clinical toxicology. The methodology is based on the same parameters which are used in pharmacokinetics. However, the interpretation and the aims are different. For each toxico n, the interpretation of kin e tic data needs to take account of the spontaneous toxicokinetics, the factors of varia tion, the relationship kinetic d ata and symptoms, the severity and prognosis criteria. The evaluatio n of treatment has to take account of the global kinetic action of the toxicon during the intoxicatio n and the effects on the symptomatology. The mechanism of toxicity, is an essential item in the interpretation of toxicokine tic data. By the exact knowledge of toxicokinetics, it is possible to determine for each toxicon, the relevant parameters which will be of use in clinical practice.
INTRODUCTION In clinical toxicology, kinetic studies should help answer the following questions : Is the symptomatology of the patient correlated with kinetic data and especially with the serum or blood concentrations? Is the kinetic profile of the patient similar or different from the spontaneous toxicokinetic ? • Service de Reanimation Medicale et Cen tre An ti· Poisons - Pavilion Pasteur - l place de l'H6pital - 67091 Stra bourg Cedex - France
Which patient will benefit from specific treatments such as enhanced drug elimination or antidotes ? Which kinetic parameter will be of use to identify this patient ? A rational approach to the toxicokinetics requires, in each case, the assessment of the global kinetic of the toxicon during the intoxication. The interpretation of analytical data needs knowledge of, for each toxicon, the spontaneous toxicokinetic, its variations, the relations between symptomatology and kinetic data, the prognostic criteria. Moreover the interpretation has to take into account the mechanism of toxicity. METHODOLOGY OF TOXICOKINETI CS The methodology includes biological sample collection, specific analytical methods and calcul ations of kinetic parameters. Sample collection and timing need special attention and have to be adapted to each toxic. For a complete toxicokinetic study it is necessary to perform analysis in various biological fluids : blood or serum urine gastric lavage fluid, dialysate fluid, blood from the inlet and outlet sides of the dialyser or the he moperfusion column. Analysis of other biological samples such as feces or cerebrospinal fluid may sometimes be interesting.
2 The diffe rent toxicokinetic parameters are calculated according to the equations shown in table I (1, 2).
Plasma kinetics. Most drugs or toxicons are eliminated from the body according to a first order kinetic (equation 1). The plasma half life (equation 2) is more conveniently applied to the clinical use than the elimination rate. If the plasma concentration cuive shows several slopes, it denotes a multicompartment kinesis which may be due to a distribution phase or to several elimination rates. An increase of the concentrations at the initial phase of the intoxication is mostly due to a continuation of the gastrointestinal absorption of the toxicon. Clearances. In ordre to estim ate th e re pective importance of the differe nt excretory routes it is essenti al to compare renal and hemodialysi or hemoperfu ion clearances with th e total body clearance (eq uation 3-4·6). If a toxicon i eliminated by renal route and hepatic metabolism, the he patic or metabolic clearance can be calculated as hown in equation 5. For the calculation of the hemody ly i or hemope rfu sion clearances it is also essential to u e eith er the erum or the blo d flow rate through the device according to the concentration which have been measured in the serum or in the whole blood. If the drug is analy ed in se rum , calculations u ing th e blo d flow rate may lead to an overe tim ation of the cleara nce and of the effici ency of th e method. Amounts eliminated. The amounts eliminated by the different routes or by speci fic treatme nt are calculated according to the equations 7-8- 9. The e amount are often compared with the amount ingested. ff a part of the toxicon ha been eliminated by gastric lavage, a compari on with th e amount potentially absorbed (equation I0) i more accurate. However in mo t ca es the exact amount ingested is not exactly known, and a part of the toxicon may have been eliminated by vomiting or has bee n
TOXICOKJNETICS IN CLINICAL TOXICOLOGY
metabolized by the liver during the first passage. Thus, in these cases it is interesting to calculate the amount bioavailable at a given time of the intoxication (equation 11) or to estimate retrospectively the total amount bioavailable namely the total amount eliminated during the intoxication (equation 12).
RESULTS AND CLINI CAL APPLI ATIONS In intoxicated patients, the kinetics of a drug may be quite different from the kinetic afte r therapeutic do es (1, 3). Indeed, the amount of drug ingested and symptoms such as a circulatory failure, a hypoxemia may strongly influence spontaneous kinetic · and especially the intestinal absorption, the renal excretion and the hepatic metabolism. Thus the study of the spontaneous toxicokinetic is an essential step for the determination of the kinetic parameters which will later be used as references for the studies of the variations, factors, of the prognostic criteria and of treatment efficiency. The following examples show several applications of toxicokinetics in clinical toxicology. 1. SPONTANEOUS TOXICOKJNETICS
Phenobarbital intoxication. Figure 1 shows an example of spontaneous kinesis in a 46-year-old man with an overdose of 6 g of phenobarbital. Plasma concentrations decreased only after the 32nd hour post ingestion with an apparent half life of 39.5 hours. The estimated half life of aborption was 5.9 hours. Twenty-six per cent of the drug ,absorbed was eliminated in urine and 74 per cent by hepatic metabolism. In this case, the total amount eliminated by the different routes (5,75 g) was very close to the as urned amount ingested (6 g).
Quinine intoxication. A 32-year-old man treated for acute malaria was admitted after an accidental overdose of 5 g intravenous
3
TOXJCOKJNETICS IN CLINICAL TOXICOLOGY
quinine (figure 2). The kinetic data (plasma half life, volume of distribution, clearances) were similar to the parmacokinetic parameters. Therefore, the quinine kinetic seems not to be dose related.
2. KJNETIC VA RIATIONS The sponta neous kinetic of a toxicon may be changed by num erous factors : dose ingested,age, sex, other drugs ingested, symptoms. Zero order kinetics have been reported in theophyllin e a nd sa licylate massive overdoses ( 4). The plasma half life of flunitrazepam increases according to the dose ingested probably because th e gastrointe tinal absorption is increased or because the hepatic metabolism is progressively saturated (5). The plasma half-life of triazolam is also increased when other psychotropic drugs have been ingested (1). In meprobamate overdose, the meprobamate plasma half life is strongly increased and the total, renal and metabolic clearances are ) decreased when barbiturates have also been ingested or when there is a circulatory failure (6). The elimination of theophylline ' is also strongly decreased in patients with congestive heart failure (table 2). In order to enhance the drug elimination in these patients with a circulatory failure, it is as important to correct the shock as to pe rform a hemodialysis or a hemoperfusion.
half life decreased from 7 to.4.5 hours after the administration of oral activa ted charcoa l. Howeve r a fall in plasma concentrations or a decrease of th e plasma half life is not definite evidence of treatment efficiency. In a case of secobarbital overdose (figure 4) the plasma concentration decreased during hemodialysis although no secobarbital was e limin ated by this route. The fall in plasma co nce ntration was due to a stop of the gastrointestin al absorption. The case of theophylline overdose in a 26-year-old man reported in table 3 shows the int erest of a com pl ete kinetic study. The plasma peak conce ntration occured only at the 11th ho ur post ingestion because of the slow absorption of the susta in ed re lease form of th eophylline. Therefore the gastric lavage pe rform ed at 1.5 hour post-ingestion, e limin ated 25.5 per cent of the amount ingested. The hemodialysis re moved 10.9 pe r cent of the potentially absorbed amount. Howeve r the he modia lysi clearance was lowe r th an the total and me tabolic clearances indicating that the major part of theophyllin e was e liminated by hepatic me tabolism. The calculated amount of theophylline e limin ated by hemodialysis was close to the amount measured in dialysate fluid s. This confirms th e accuracy of th e calculation me thod (equ ation 9) using the se rum concentration and th e serum flow rate through the dialyser.
3. EVALUATION OF TREATMENT The evalu ation of th e el imin ation me thods should be based not only on clinical improve me nt, high clea rances values, decrease of pla ma concentrations a nd half life, but also on the amounts of toxicon e liminated by the diffe rent routes (1, 4, 7, 8, ' 9). Sometimes however this methodology is not applied to the type of treatment. For instance the effect of oral activated charcoal can only be estimated by the variations of plasma concentrations, half lives and total clearances (10). In the case of theophylline intoxication reported in figure 3, the plasma
4. BIOAVAILABLE AMOUNTS Calculation of the bioavailable amounts may have several uses. The total amount bioava ilable (ABT) or the amount bioavailable at plasma peak concentration (ABT) may be compared with the amounts ingested (1). Calculation of the amounts bioavailable at given times may also be used for the estimation of the amount of drug metabolized during a treatment with hemodialysis or hemoperfusion (7). A study performed in 13 cases of phenobarbital intoxication showed that the calculated total
4
TOXTCOKJNETICS IN CLINICAL TOXICOLOGY
TABLE 1: CALCULATION OF TOXICOKINETIC PARAMETERS PLASMA KINETIC * Plasma (blood) concentration curve Equation 1:
Cpt
= Cpo (e - K•t)
* Plasma (blood) half life T 112
Log2 Ke
Equation 2 :
=--
CLEARANCES *Total body clearance (CIT) Equation 3:
CIT log 2 x VD x W T112
* Renal clearance (CIR)
Ke x VD x W
Cu x Qu Cp
Equation 4: * Metabolic clearance (CIM) Equation 5 :
* Hemodialysis or hemoperfusion clearance (CIHo) · 6: Cl Ho = __. C;. Cou1) .;.;.;._- ____;, ,;;.;.;Qs . . __ E quatton
cin
AMOUNTS ELI MINATED * In urine (Au) Equation 7 :
Au
=
AM
=
Cu x Vu
*By hepatic metabolism (AM) Equation 8:
Au
X CIM CIR
* By hemodialysis or hemoperfu ion (A 110 ) Equation 9:
CLim x Cin
A Ho
X
AMOUNT POTENTIALLY ABSORBED (AA) Equation 10 : BIOAV AILABLE AMOUNT * Bioavailable amount at time t quation 11:
A 81
= CP, x
AeT
=
* Total available amount Equation 12 :
C4 x Cl
x
VD Au R
W
THO
)
5
TOXICOKINETICS IN CLINICAL TOXICOLOGY
amounts eliminated during the intoxication (ABT) correlated well with the plasma peak concentrations and with the bioavailable amounts calculated with the plasma peak concentration (ABT) (figure 5-6). These results show that in phenobarbital intoxication, the plasma peak concentration is a relevant parameter for the estimation of the amount of bioavailable phenobarbital. INTE RPRETATION The interpretation of kinetic data has also to take into account the mechanism of toxicity (5). For this purpose, three classes of toxicons can be distinguished : the functional toxicons, th e lesional toxicons and the toxicons which may act by both mechani sms. I. FUNCTIONAL TOXJCONS
Barbiturates, mepro ba ma te, be nzodiazepines, cardiotropic drugs, lithium for instance act as function al toxicons. They impair the function of one or several organs and the patients recover without sequelae if no complications have occured during the intoxication. Their toxicity is directly related to the concentration at the targe t or rece ptor and the subsequent evolution is depe ndent on the elimination of the toxicon from these fixation sites. Symptoms occur only when the plasma or blood concentration is higher than a de finite threshold and their seve rity increases according to the concentrations (figure 7). The duration of the symptoms is dependent on the plasma or blood half life and on the elimination of the toxicon. The aim of the treatm ent is to decrease the conce ntration of the toxicon at the targe t organs and to enhance the elimination from the body. For most functional toxicons there is a good relationship between plasma or blood concentrations and symptomatology. However this relationship may be changed by several factors such as active or toxic metabolites, cause of the intoxication, underlying diseases, age. For instance
in amitriptyline overdoses, the underestimation of the active metabolite, nortriptyline, may lead to a gap between cardiac symptoms and plasma concentrations (11 ). For th eophylline, lithium, phenobarbital, th e relationship symptomatology-plasma concentrations is different if the intoxication is acute, chronic or acute upon chronic (12, 13). An underlying cardiac disease is an aggravating factor in poisoning with cardiotoxic drugs. In these patients, cardiotoxicity may appear at lower concentrations than in patients without cardiac dis~ase (14). The effects of treatment can be deducted from the kinetic data. For toxicons with high total clearance and high rate of hepatic metabolism, forced diuresis or extracorporeal elimination methods will be of little use in order to enhance the elimination (1, 4). For many drugs, the amounts eliminated by hepatic metabolism are higher than the amounts removed by hemodialysis or hemoperfusion (1, 7). A comparison of the clearances of 5 barbiturates show that the differences in total clearance values are related to the different rates of hepatic metabolism (table 4). These data indicate that the elimination of phenobarbital only will be significantly increased by forced diuresis, hemodialysis or hemoperfusion. 2. LESIONAL TOXICONS
Paraqu at, amatoxins, colchicine and most heavy metals are typical examples of toxicons which cause organ or cellular damage. Thei r toxicity is dependent on the maximal concentration reached at the target organ. Symptoms do not always improve eve n though the toxicon is eliminated from the target organ or the body because cellular damage has occured before. Severity, prognosis and indications of treatment can only be determinated by the estimation of plasma concentrations and kinetic data in relation to time after ingestion or exposure. The same plasma concentration may be non
6 toxic, toxic or lethal according to the time at which the concentration is measured (figure 8). Paraquat is a typical example of the contribution of toxicokinetic to the . assessment of prognostic criteria (15). Plasma paraquat concentrations related to time since ingestion are a good indication for severity and prognosis. Treatment which enhances the toxicon elimination will only be efficient if they are administered before severe cellular damage has oe
