Allometric Pharmacokinetic Scaling: Towards the Prediction of Human Oral Pharmacokinetics

Purpose. To evaluate (1) allometric scaling of systemic clearance (CL)using unbound drug concentration, (2) the potential usage of brainweight (BRW) correction in allometric scaling of both CL and oralclearance (CL/F). Methods. Human clearance was predicted allometrically (CLu = a ·W^biv) using unbound plasma concentration for eight Parke-Daviscompounds and 29 drugs from literature sources. When the exponent b_ivwas higher than 0.85, BRW was incorporated into the allometricrelationship (CLu*BRW = a · W^biv). This approach was also applied tothe prediction of CLu/F for 10 Parke-Davis compounds. Human oralt1/2, Cmax, AUC, and bioavailability were estimated based onallometrically predicted pharmacokinetic (PK) parameters. Results. Human CL and CL/F were more accurately estimated usingunbound drug concentration and the prediction was further improvedwhen BRW was incorporated into the allometric relationship. ForParke-Davis compounds, the predicted human CL and CL/F werewithin 50-200% and 50-220% of the actual values, respectively. Theestimated human oral t1/2, Cmax, and AUC were within 82-220%,56-240%, and 73-190% of the actual values for all 7 compounds,suggesting that human oral PK parameters of those drugs could bereasonably predicted from animal data. Conclusions. Results from the retrospective analysis indicate thatallometric scaling of free concentration could be applied to orallyadministered drugs to gain knowledge of drug disposition in man, and to helpdecision-making at early stages of drug development.     

A comparison of the effects of fentanyl and alfentanil on the sleeping times of the intravenous induction agents

The effect of increasing doses of fentanyl and alfentanil administered before four intravenous induction agents (thiopentone, methohexitone, Althesin and etomidate) on the sleeping time were studied in mice. A biphasic pattern of sleeping time was noted with the more rapidly metabolized and eliminated compounds. Possible explanations are discussed.     

Propofol. A review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic

Propofol is an intravenous anaesthetic which is chemically unrelated to other anaesthetics. Induction of anaesthesia with propofol is rapid, and maintenance can be achieved by either continuous infusion or intermittent bolus injections, with either nitrous oxide or opioids used to provide analgesia. Comparative studies have shown propofol to be at least as effective as thiopentone, methohexitone or etomidate for anaesthesia during general surgery. The incidence of excitatory effects is lower with propofol than with methohexitone, but apnoea on induction occurs more frequently with propofol than with other anaesthetics. Additionally, a small number of studies of induction and maintenance of anaesthesia have found propofol to be a suitable alternative to induction with thiopentone and maintenance with halothane, isoflurane or enflurane. Propofol is particularly suitable for outpatient surgery since it provides superior operating conditions to methohexitone (particularly less movement), and rapid recovery in the postoperative period associated with a low incidence of nausea and vomiting. When used in combination with fentanyl or alfentanil, propofol is suitable for the provision of total intravenous anaesthesia, and comparative studies found it to be superior to methohexitone or etomidate in this setting. Infusions of subanaesthetic doses of propofol have been used to sedate patients for surgery under regional anaesthesia, and also to provide sedation of patients in intensive care. In the latter situation it is particularly encouraging that propofol did not suppress adrenal responsiveness during short term studies. If this is confirmed during longer term administration this would offer an important advantage over etomidate. Thus, propofol is clearly an effective addition to the limited range of intravenous anaesthetics. While certain areas of its use need further study, as would be expected at this stage of its development, propofol should find a useful role in anaesthetic practice.     

The effect of anaesthetics on the uptake and release of gamma-aminobutyrate and D-aspartate in rat brain slices.

1 The effect of various concentrations of thiopentone, pentobarbitone, methohexitone, hydroxydione, alphaxalone/alphadolone, ketamine, alpha-chloralose, and urethane on the transport of radiolabelled gamma-aminobutyric acid (GABA) and D-aspartate was investigated. 2 Uptake of the amino acids was weakly inhibited, if at all, by the anaesthetics and it is unlikely that such effects contribute significantly to their physiological function. 3 The spontaneous efflux of GABA and D-aspartate was not detectably altered by any of the drugs tested. 4 Thiopentone, pentobarbitone, methohexitone and hydroxydione inhibited K+-stimulated GABA and D-aspartate release. The other anaesthetics had no effect on K+-stimulated amino acid release. 5 The rank order of potency of the inhibitors of K+-stimulated amino acid release did not correlate with their anaesthetic potency. Furthermore not all inhibitors appeared to be very effective at anaesthetic concentrations. 6 It is concluded that although it is possible that inhibition of excitatory transmitter release may be involved in the anaesthetic action of some anaesthetics, for many of the substances tested in this study such as mechanism does not appear to be implicated.     

Alfentanil potentiates anaesthetic and electroencephalographic responses to ketamine in the rat

The interactions between mu-opioid and N-methyl-D-aspartate (NMDA) receptors have important implications for clinical pain management. We recently examined the pharmacokinetics of ketamine in rats following i.v. infusion of ketamine (racemate, 50 mg/kg/5 min) and found increased central nervous system distribution of ketamine in the presence of low constant plasma alfentanil concentrations (approximately 50 ng/ml). We now report on the effects of low plasma alfentanil concentrations on the duration of anaesthetic and electroencephalographic (EEG) responses to i.v. infusion of ketamine. Compared to ketamine alone, alfentanil significantly increased both the duration of anaesthesia (by 130%, P=0.00022) and the processed EEG power (microV(2)/s) (by 48%, P=0.0040). The plasma ketamine concentration producing half-maximal EEG effect was significantly reduced (by 60%, P<0.0001) in the presence of alfentanil. The results indicate that low plasma alfentanil concentrations potentiate the anaesthetic and EEG effects produced by ketamine.     

EFFECTS OF HALOTHANE, KETAMINE, PROPOFOL AND ALFENTANIL ANAESTHESIA ON CIRCULATORY CONTROL IN RABBITS

1. We have made a within-rabbit comparison of the effects of four general anaesthetic regimens on the haemodynamic response to acute reduction in central blood volume and on baroreflex control of heart rate. 2. Acute haemorrhage was simulated by gradually inflating a cuff on the inferior vena cava in order to cause cardiac output to fall at a constant rate of 8.5%/min while the responses of systemic vascular resistance, arterial pressure and heart rate were measured. The full range of the baroreceptor-heart rate reflex was elicited by inflating aortic and vena caval cuffs. These indices of circulatory control were repeatedly measured within five protocols, to which each rabbit was exposed in randomized order. 3. In each protocol the rabbit was first studied unanaesthetized. Then a small dose of thiopentone sodium was given (16 mg/kg). In the four main protocols the rabbit was then intubated and ventilated, first with 100% oxygen and then with 50% nitrous oxide, during administration of one of four anaesthetic agents. These were halothane (2.0 and 2.5%), ketamine (2.5 mg/kg per min), propofol (0.83 and 1.25 mg/kg per min) and alfentanil (2.5 and 3.33 micrograms/kg per min). In a sham protocol the effects of 100% oxygen, then those of 50 and 75% nitrous oxide, were studied while the rabbit remained conscious. 4. In unanaesthetized rabbits, in the presence or absence of nitrous oxide, the normal biphasic haemodynamic response to simulated haemorrhage occurred. The first, vasoconstrictor, phase was attenuated by halothane, ketamine and propofol, so that arterial pressure fell more steeply than normal. Not only was the vasoconstrictor phase unaffected by alfentanil but it was extended, so that arterial pressure remained at a normal level even when cardiac output had fallen by 59%. This effect of alfentanil appeared to be mediated centrally, since it could be reproduced by injecting small doses (1.5-7.5 micrograms) into the fourth ventricle. All four anaesthetic agents and nitrous oxide attenuated the baroreceptor control of heart rate. The effect was least with nitrous oxide and alfentanil, greatest with halothane.     

Correlation of intrinsic in vitro and in vivo clearance for drugs metabolized by hepatic UDP-glucuronosyltransferases in rats

A method for quantitatively predicting the hepatic clearance of drugs by UDP-glucuronosyltransferases (UGTs) from in vitro data has not yet been established. We examined the relationship between in vitro and in vivo intrinsic clearance by rat hepatic UGTs using 10 drugs. For these 10 drugs, the in vitro intrinsic clearance by UGTs (CL(int, in vitro)) measured using alamethicin-activated rat liver microsomes was in the range 0.10-4500 ml/min/kg. Microsomal binding (f(u, mic)) was determined to be in the range 0.29-0.95 and the unbound intrinsic clearance (CL(uint, in vitro)) to be in the range 0.11-9600 ml/min/kg. The contribution of rat hepatic glucuronidation to drug elimination was 12.0%-76.6% and in vivo intrinsic clearance by UGTs was 5.7-9000 ml/min/kg. To evaluate the discrepancy between the in vitro and in vivo values, a scaling factor was calculated (CL(int, in vivo)/CL(int, in vitro)); the values were found to be in the range 0.89-110. The average fold error of the scaling factor values incorporating f(u, mic) was closer to unity than that without f(u, mic). The scaling factor values incorporating f(u, mic) were <10 in 8/10 drugs and <2 in 6/10 drugs, indicating a small discrepancy between in vitro and in vivo values. Thus, using alamethicin-activated liver microsomes, incorporating f(u, mic) into CL(int, in vitro), and considering the contribution of glucuronidation may enable us to quantitatively predict in vivo hepatic glucuronidation from in vitro data.     

Convulsive thresholds in mice during the recovery phase from anaesthesia induced by propofol, thiopentone, methohexitone and etomidate.

1. Convulsive thresholds were measured with intravenous pentylenetetrazol in mice during the recovery phase after intravenous anaesthetic doses of propofol (10 and 20 mg kg-1), thiopentone (30 mg kg-1), methohexitone (10 mg kg-1), and etomidate 3 mg kg-1). 2. The convulsive threshold rose after each agent, indicating an anticonvulsant action for all the drugs tested; this declined to control values with initial half times of: 1.56 min (propofol 10 mg kg-1); 1.03 min (propofol 20 mg kg-1): 1.02 min (methohexitone); 3.35 min (etomidate); 13.7 min (thiopentone). 3. At no time during the recovery phase of any agent did the convulsive threshold fall below control values, which might indicate an epileptogenic effect of the drug. 4. The threshold was depressed below control values by intravenous administration of Ro 15-4513, a partial inverse agonist at the benzodiazepine receptor, thus indicating the ability of this pentylenetetrazol test to demonstrate a proconvulsant effect. 5. We conclude that the abnormal movements or convulsions associated with recovery from anaesthesia with short-acting intravenous anaesthetics may not be the result of an intrinsic proconvulsant action of the drugs.     

Prediction of cytochrome p450-mediated hepatic drug clearance in neonates, infants and children : how accurate are available scaling methods?

Correct dosing of drugs in neonates, infants and children is hampered by a general lack of knowledge about drug disposition in this population. Suggested methods to improve our knowledge without performing conventional full-scale investigations include population pharmacokinetic studies, allometric scaling of drug disposition according to bodyweight and in silico prediction of pharmacokinetics. The last method entails scaling of pharmacokinetic parameters according to age-dependent changes in drug absorption and elimination capacity, plasma protein binding and physiological characteristics of the subjects. Maturation (or ontogeny) of the drug-metabolising part of the cytochrome P450 (CYP) enzyme system is thus an important factor in the calculations for most drugs. The aim of this commentary is to test and critically examine the proposed methods to estimate hepatic clearance (CL) as a function of age (0-20 years), with CYP3A-mediated metabolism as the case in point. Midazolam and alfentanil were used as model drugs.Allometric scaling failed to predict the CL of midazolam and alfentanil in neonates. Calculations using in vitro findings on CYP maturation gave better estimates for neonates but very divergent ones for older infants and children. This was chiefly due to very different data on CYP3A4/5 ontogeny in three published studies. In the age range where full adult CYP activity per gram of liver could be assumed, allometric scaling and in silico predictions gave similar results. These predictions were also in approximate agreement with clinical data.The findings with the two model drugs can very probably be generalised to most drugs cleared by CYP-dependent hepatic metabolism. Allometric scaling accounts for development of body size and function but not for the fact that the drug-metabolising capacity of the liver is generally low at birth. The crucial question in the prediction of CL is thus when the activity of the applicable CYP isoform(s) attains adult levels. There are still not enough data on this, particularly when different studies even on the same CYP isoform have given very divergent results. It may also be pointed out that CYP ontogeny is an area where we have at least some information. There are several other important developmental changes about which we know practically nothing. Thus, while allometric scaling is generally unreliable for prediction in neonates and infants, the alternative method of in silico prediction can at present be used only to obtain tentative initial estimates of drug CL. Neither of the methods can be used as a substitute for actual clinical studies.     

A unified model for predicting human hepatic, metabolic clearance from in vitro intrinsic clearance data in hepatocytes and microsomes.

The aim of this study was to evaluate a unified method for predicting human in vivo intrinsic clearance (CL(int, in vivo)) and hepatic clearance (CL(h)) from in vitro data in hepatocytes and microsomes by applying the unbound fraction in blood (fu(b)) and in vitro incubations (fu(inc)). Human CL(int, in vivo) was projected using in vitro data together with biological scaling factors and compared with the unbound intrinsic clearance (CL(int, ub, in vivo)) estimated from clinical data using liver models with and without the various fu terms. For incubations conducted with fetal calf serum (n=14), the observed CL(int, in vivo) was modeled well assuming fu(inc) and fu(b) were equivalent. CL(int, ub, in vivo) was predicted best using both fu(b) and fu(inc) for other hepatocyte data (n=56; r(2)=0.78, p=3.3 x 10(-19), average fold error=5.2). A similar model for CL(int, ub, in vivo) was established for microsomal data (n=37; r(2)=0.77, p=1.2 x 10(-12), average fold error=6.1). Using the model for CL(int, ub, in vivo) (including a further empirical scaling factor), the CL(h) in humans was also calculated according to the well stirred liver model for the most extensive dataset. CL(int, in vivo) and CL(h) were both predicted well using in vitro human data from several laboratories for acidic, basic, and neutral drugs. The direct use of this model using only in vitro human data to predict the metabolic component of CL(h) is attractive, as it does not require extra information from preclinical studies in animals.     

The preparation and intravenous anaesthetic activity of tetrahydrofuran-3-ols

A number of tetrahydrofuran-3-ols have been prepared and examined for intravenous anaesthetic activity. The compounds studied had low intrinsic anaesthetic activity and there was an inverse relation between anaesthetic activity or toxicity and solubility in water. It was considered unlikely that compounds comparable in activity to thiopentone or methohexitone would be found in this series.     

Differential influence of laboratory anaesthetic regimens upon renal and hepatosplanchnic haemodynamics in the rat

Renal blood flow in rats anaesthetized with the combination alphaxolone/alphadolone (3.90 mL min-1 (g tissue)-1) was significantly (P less than 0.05) greater than in rats anaesthetized with ketamine midazolam (3.24 mL min-1 (g tissue)-1, pentobarbitone (3.19 mL min-1 (g tissue)-1), fentanyl/fluanisone midazolam (2.84 mL min-1 (g tissue)-1) or urethane (1.99 mL min-1 (g tissue)-1). Renal blood flow in the urethane anaesthetized rats was significantly (P less than 0.05) lower than in animals anaesthetized with the other anaesthetic regimens, and is consistent with literature reports of a depressive effect of urethane anaesthesia upon xenobiotic renal clearance in the rat. Hepatosplanchnic blood flow was highest in the alphaxolone/alphadolone anaesthetized animals (71.7 mL min-1 kg-1), with the urethane anaesthetized animals demonstrating a significantly (P less than 0.05) lower (33.4 mL min-1 kg-1) blood flow. The fentanyl fluanisone/midazolam (65.4 mL min-1 kg-1), pentobarbitone (61.1 mL min-1 kg-1), and ketamine/midazolam (51.4 mL min-1 kg-1) regimens resulted in hepatosplanchnic blood flows of intermediate magnitude. The observed marked differential effects of the anaesthetic regimens upon renal and hepatosplanchnic blood flows may dramatically influence drug disposition in the experimental animal, and be of significance to laboratory pharmacokinetic studies in which anaesthesia is used.     

Biotransformation of ketamine, (Z)-6-hydroxyketamine, and (E)-6-hydroxyketamine by rat, rabbit, and human liver microsomal preparations

1. (Z)- and (E)-6-Hydroxyketamine have been synthesized and their metabolism by hepatic microsomal preparations studied to elucidate the metabolism of ketamine. 2. Both 6-hydroxyketamines are exclusively converted to 6-hydroxy-norketamines by N-demethylation. The g.l.c. retention properties and mass spectral characteristics of these 6-hydroxy-norketamines were used to confirm the structures of ketamine metabolites. 3. Ketamine is converted to norketamine, 4-, 5- and 6-hydroxynorketamines and possibly 4- and 6-hydroxyketamines in hepatic microsomal preparations from rats, rabbits and man. Norketamine is the major metabolite in all species tested. 4. 6-Hydroxynorketamine is the major hydroxylated metabolite and is found only in the (Z)-form in the species examined. 5. The metabolism of ketamine and the 6-hydroxy-ketamines is greatly increased after phenobarbital pretreatment of rats and rabbits.     

Differential Effects of Anesthetic Regimens on Gentamicin Pharmacokinetics in the Rat: A Comparison with Chronically Catheterized Conscious Animals

The intravenous disposition of gentamicin was compared in the conscious chronically catheterized rat with that in rats anesthetized using five injectable laboratory anesthetics. Gentamicin plasma clearance in the conscious rat was significantly higher than in animals anesthetized with urethane, fentanyl/ fluanisone/midazolam, pentobarbitone, or ketamine/midazolam but similar to that in rats anesthetized with alphaxolone/alphadolone. Urethane anaesthesia resulted in a significantly lower gentamicin clearance than in all other groups. Gentamicin clearance in rats anesthetized with alphaxolone/alphadolone was significantly higher than in rats anesthetized with either fentanyl/fluanisone/midazolam or urethane. No significant differences in the volume of distribution of gentamicin were observed between any of the groups studied, either anesthetized or conscious. Carboxyinulin blood clearance in the conscious group was significantly higher than that with urethane, fentanyl/fluanisone/midazolam, pentobarbitone, or ketamine/midazolam but not significantly different from alphaxolone/ alphadolone-anesthetized animals. The differences in carboxyinulin clearance were noted to be proportional to the differences in gentamicin clearance (r ² = 0.98). These results demonstrate that the choice of anesthetic used in laboratory pharmacokinetic studies is important. Gentamicin clearance was higher in conscious than anesthetized rats, and it may be prudent to use chronically catheterized animals in pharmacokinetic studies.     

Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.

We investigated the quantitative prediction of human hepatic metabolic clearance from in vitro experiments focusing on cytochrome P450 metabolism with eight model compounds, FK1052, FK480, zolpidem, omeprazole, nicardipine, nilvadipine, diazepam, and diltiazem. For the compounds, in vivo human hepatic extraction ratios ranged widely from 0.03 to 0.87. In vitro and in vivo hepatic intrinsic clearance (CL(int)) values for each compound were measured and calculated in rats and/or dogs and humans. CL(int,in vitro) was determined from a substrate disappearance rate at 1 microM in hepatic microsomes, which was a useful method. CL(int,in vivo) was calculated from in vivo pharmacokinetic data using three frequent mathematical models (the well stirred, parallel-tube, and dispersion models). The human scaling factor values (CL(int,in vivo)/CL(int,in vitro)) showed marked difference among the model compounds (0.3-26.6-fold). On the other hand, most of the animal scaling factors were within 2-fold of the values in humans, suggesting that scaling factor values were similar in the different animal species. When human CL(int,in vitro) values were compared with the actual CL(int,in vivo), correlation was not necessarily good. By contrast, using human CL(int,in vitro) corrected with the rat and/or dog scaling factors yielded better predictions of CL(int,in vivo) that were mostly within 2-fold of the actual values. Furthermore, successful predictions of human CL(oral) and hepatic extraction ratio (E(H)) were obtained by use of the human CL(int,in vitro) corrected with animal scaling factors. The new variant method is a simple one, incorporating additional information from animal studies and providing a more reliable prediction of human hepatic clearance.     

Anaesthetic, cardiovascular and respiratory effects of a new steroidal agent CT 1341: A comparison with other intravenous anaesthetic drugs in the unrestrained cat

1. The anaesthetic, cardiovascular, respiratory and adverse effects produced by the intravenous injection of CT 1341, thiopentone, methohexitone, pentobarbitone, propanidid and ketamine have been compared in unrestrained cats prepared with chronically implanted venous and arterial cannulae. Aortic blood pressure and heart rates were monitored before, during and after loss of consciousness.2. CT 1341 produced rapid induction of anaesthesia followed by moderately rapid recovery, was active over a wide range of doses and caused minimal respiratory depression and few adverse effects. It caused an initial short-lasting tachycardia and fall in aortic blood pressure succeeded by a secondary depressor response.3. The safety margin was narrower with the barbiturate drugs than with CT 1341, and large doses induced apnoea and respiratory depression. Small doses of methohexitone elicited excitatory effects and large doses caused severe respiratory and circulatory depression, and recovery from anaesthesia was protracted.4. Propanidid induced short-lasting light anaesthesia. The safety margin was narrowest with this drug and induction was associated with adverse circulatory, respiratory and other effects.5. Ketamine was active over a wide range of doses but exhibited qualitatively different properties from the other anaesthetics. Induction was slower after small doses and these produced circulatory stimulation, catatonia and bizarre behavioural effects. Large doses caused respiratory and circulatory depression and recovery was protracted.6. It is concluded that CT 1341 has a wider therapeutic latitude, produces less respiratory depression and has other advantages over the currently used intravenous anaesthetics.     

The effects of anaesthetics on the uptake and release of amino acid neurotransmitters in thalamic slices

1 The effect of thiopentone, methohexitone, urethane and ketamine on the uptake and release of gamma-aminobutyric acid (GABA) and D-aspartate by rat thalamic slices has been investigated. 2 A high, supra-anaesthetic concentration of methohexitone increased the uptake of both D-aspartate and GABA. 3 None of the anaesthetics used had any detectable effect upon the spontaneous release of either amino acid. 4 Urethane and ketamine had no effect upon the K+-stimulated release of either amino acid. 5 Methohexitone and thiopentone produced a biphasic dose-response on the K+-stimulated release of both amino acids; low concentrations enhanced release, high concentrations depressed release. 6 Bicuculline hydrochloride and picrotoxin both significantly reduced the barbiturate-induced enhancement of K+-stimulated amino acid release, but did not significantly alter the depression of K+-stimulated release at higher barbiturate concentrations. 7 Baclofen, either alone (1 microM to 1 mM), or tested against the barbiturates, had no detectable effect.     

Effects of Long-Term Drugs on Alfentanil Clearance in Patients Undergoing Renal Transplantation

Although patients in renal failure frequently take several drugs on a long-term basis, drug-induced alterations in alfentanil metabolism have not been examined as a possible source of variability in alfentanil clearance in this population. We compared the pharmacokinetics of alfentanil during renal transplantation in seven patients receiving and six not receiving long-term drug therapy. After the rapid intravenous injection of alfentanil 100 μg/kg during isoflurane anesthesia, plasma concentrations were measured at intervals up to 6 hours by radioimmunoassay. The terminal elimination half-life, steady-state volume of distribution (Vd_ss), and total body clearance were determined by non-compartmental methods. There was no statistical difference in the Vd_ss between the two patient groups. However, clearance was significantly higher and elimination half-life lower in the group taking long-term drugs: clearance 6.94 ± 4.64 versus 3.47 ± 0.16 ml·kg⁻¹·min⁻¹, and elimination half-life 50.6 ± 13.9 versus 90.7 ± 22.4 minutes, respectively (p<0.05). The higher clearance occurred even though five of the seven patients were taking agents known to be metabolized by the same cytochrome P-450 hepatic isozyme that metabolizes alfentanil and therefore potential competitive inhibitors of alfentanil metabolism. Drugs taken by the three patients with the highest alfentanil clearances included known inducers of hepatic drug metabolism. Thus, in the presence of several long-term drugs, the clearance of alfentanil appears to be noticeably increased by inducers of hepatic drug metabolism but unaffected by potential competitive inhibitors.     

Comparative physiological pharmacokinetics of fentanyl and alfentanil in rats and humans based on parametric single-tissue models

The objectives of this investigation were to characterize the disposition of fentanyl and alfentanil in 14 tissues in the rat, and to create physiological pharmacokinetic models for these opioids that would be scalable to man. We first created a parametric submodel for the disposition of either drug in each tissue and then assembled these submodels into whole-body models. The disposition of fentanyl and alfentanil in the heart and brain and of fentanyl in the lungs could be described by perfusion-limited 1-compartment models. The disposition of both opioids in all other examined tissues was characterized by 2- or 3-compartment models. From these models, the extraction ratios of the opioids in the various tissues could be calculated, confirming the generally lower extraction of alfentanil as compared to fentanyl. Assembly of the single-tissue models resulted in a whole-body model for fentanyl that accurately described its disposition in the rat. A similar assembly of the tissue models for alfentanil revealed non-first-order elimination kinetics that were not apparent in the blood concentration data. Michaelis-Menten parameters for the hepatic metabolism of alfentanil were determined by iterative optimization of the entire model. The parametric models were finally scaled to describe the disposition of fentanyl and alfentanil in humans. Supported in part by the National Institute on Aging, RO1-AG-4594, and the Anesthesia/Pharmacology Research Foundation.     

Biotransformation of ketamine, (Z)-6-hydroxyketamine,and (E)-6-hydroxyketamine by rat,rabbit, and human liver microsomal preparations

1. (Z)- and (E)-6-Hydroxyketamine have been synthesized and their metabolism by hepatic microsomal preparations studied to elucidate the metabolism of ketamine.

2. Both 6-hydroxyketamines are exclusively converted to 6-hydroxy-norketamines by N-demethylation. The g.1.c. retention properties and mass spectral characteristics of these 6-hydroxy-norketamines were used to confirm the structures of ketamine metabolites.

3. Ketamine is converted to norketamine, 4-, 5- and 6-hydroxynorketamines and possibly 4- and 6-hydroxyketamines in hepatic microsomal preparations from rats, rabbits and man. Norketamine is the major metabolite in all species tested.

4. 6-Hydroxynorketamine is the major hydroxylated metabolite and is found only in the (Z)-form in the species examined.

5. The metabolism of ketamine and the 6-hydroxy-ketamines is greatly increased after phenobarbital pretreatment of rats and rabbits.