Disposition and exposure of the fibrinogen receptor antagonist XV459 on alphaIIBbeta3 binding sites in the guinea pig.

The disposition of XV459, a potent, selective GP IIb/IIIa antagonist, has been examined following intravenous administration of XP280, the benzenesulphonate salt, and 3H-SA202, the trifluroacetic acid salt, to male guinea pigs. A liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for XV459 quantitation in guinea pig plasma with an LLOQ of 0.1 ng/mL. Intravenous infusions (30 min) of XP280 at doses of 0.5 and 2.0 microg/kg were administered to guinea pigs which were sequentially sacrificed at 0.5, 1, 1.5, 4, 8, 12, 24, 48 and 72 h postinitiation of infusion. Maximum total (unbound and GP IIb/IIIa displaced) XV459 plasma concentration of approximately 3.5 microg/mL was obtained at the 2.0 microg/kg dose. Pooling individual concentration-time data yielded a systemic clearance of 1.42 mL/min/kg, Vss of 0.24 L/kg, and a terminal half-life of 2.8 h in the guinea pig at the 0.5 microg/kg dose. The 2.0 microg/kg dose yielded XV459 exposure that was less than proportional to the previous dose. Similar behaviour has been observed in human trials. Cumulative (up to 72 h) urinary and faecal recovery of total radioactivity was 66.4 and 11.2%, respectively. The time course of spleen, marrow and whole blood radioactivity profiles was similar, suggesting that XV459 was not preferentially sequestered on non-plasma GP IIb/IIIa binding sites. Tissue to blood ratios of 20.7 and 8.3 for the spleen and bone marrow, respectively, indicate that increased (relative to blood) exposure was evident for sites containing the GP IIb/IIIa receptor. In vitro studies confirmed the similarity of XV459 binding to both resting and activated platelets in the guinea pig and humans. Given the comparability of dissociation rate constants and IC50s based on in vitro platelet aggregation, human dosimetry estimates should assume similar partitioning of radiolabelled XV459 as in the guinea pig. These results suggest that the guinea pig may indeed be an appropriate animal model for pharmacokinetic and distribution studies with DMP754; in conjunction with recent pharmacological findings with GP IIb/IIIa antagonists, our results suggest that the guinea pig may be the rodent species of choice for preclinical studies with some other GP IIb/IIIa antagonists.

Steady-state propofol brain:plasma and brain:blood partition coefficients and the effect-site equilibration paradox.

Based on volume-flow relationships, CNS agents that are highly lipid soluble (log octanol-water partition coefficient > 2) are expected to have equilibration half-times (T1/2 kE0) that are proportional to brain solubility. Propofol, the most lipophilic anaesthetic in clinical use, has T1/2 kE0 values of 1.7 and 2.9 min in rats and humans, respectively, compared with an expected value of at least 8 min. As a first step in exploring this discrepancy between observed and predicted values, we determined the steady state brain:plasma and brain:blood partition coefficients in rats after a 4-h infusion of propofol. Brain:plasma and brain:blood partition coefficients were 8.2 (SD 1.6) and 3.0 (0.5), respectively. T1/2 kE0 predictions based on brain: blood partitioning in rats are more in agreement with the observed equilibration half-time, suggesting that drug bound to the formed elements of blood participates in the uptake and transfer of propofol to its effect site.

Formulation-dependent brain and lung distribution kinetics of propofol in rats.

BACKGROUND: Propofol when administered by brief infusion in a lipid-free formulation has a slower onset, prolonged offset and greater potency compared with an emulsion formulation. To understand these findings the authors examined propofol brain and lung distribution kinetics in rats. METHODS: Rats were infused with equieffective doses of propofol in emulsion (n = 21) or lipid-free formulation (n = 21). Animals were sacrificed at various times to harvest brain and lung. Arterial blood was sampled repeatedly from each animal until sacrifice. Deconvolution and moment analysis were used to calculate the half-life for propofol brain turnover (BT) and brain:plasma partition coefficient (Kp). Lung concentration-time profiles were compared for the two formulations. RESULTS: Peak propofol plasma concentrations for the lipid-free formulation were 50% of that observed for emulsion formulation, whereas peak lung concentrations for lipid-free formulation were 300-fold higher than emulsion formulation. Brain Kp calculated from tissue disposition curve and ratio of brain:plasma area under the curves were 8.8 and 13, and 7.2 and 9.1 for emulsion and lipid-free formulations, respectively. BT were 2.4 and 2.5 min for emulsion and lipid-free formulations, respectively. CONCLUSIONS: Significant pulmonary sequestration and slow release of propofol into arterial circulation when administered in lipid-free vehicle accounts for the lower peak arterial concentration and sluggish arterial kinetics relative to that observed with the emulsion formulation. Higher Kp for the lipid-free formulation could explain the higher potency associated with this formulation. BT were independent of formulation and correlated with values reported for effect-site equilibration half-time consistent with a distribution mechanism for pharmacologic hysteresis.

Formulation-dependent pharmacokinetics and pharmacodynamics of propofol in rats.

Propofol, a highly lipophilic anaesthetic, is commercially formulated as a lipid emulsion (diprivan) for intravenous use. This formulation is characterized by rapid onset and offset of effect after rapid intravenous administration and an effect-site equilibration half-life (t1/2kE0) of 1.7 min in rats. Paradoxically these characteristics are usually associated with relatively water-soluble anaesthetics. To test the influence of the formulation on propofol pharmacokinetics, effect-site equilibration kinetics and pharmacodynamics we performed a pharmacokinetic-pharmacodynamic study of propofol in chronically instrumented rats after administration in a lipid-free formulation. In this report we present the results of this study and compare these results with previous data obtained with rats receiving propofol in the emulsion formulation. Compared with the emulsion formulation the distribution volumes (VdC and VdSS) were significantly higher but the t1/2kE0 (2.0 min) was similar for the lipid-free formulation. The concentration-effect relationship was biphasic. Propofol effect-site concentrations required to achieve 50% activation, peak activation, 50% inhibition of peak activation effect and maximum inhibition were significantly lower, indicating a higher apparent steady-state potency for the lipid-free formulation compared with the emulsion formulation. The evanescent characteristics of propofol's effect-time-course disappeared when the anaesthetic was administered in the lipid-free formulation. These results suggest that the nature of the formulation can profoundly influence the clinical characteristics of intravenously administered drugs by modifying the pharmacokinetics or pharmacodynamics or both.

Precursor-dependent indirect pharmacodynamic response model for tolerance and rebound phenomena.

A precursor-dependent model of indirect pharmacodynamic response which can describe tolerance and rebound was characterized in terms of the effects of changes in the fundamental properties of the drug on its response profiles. The model extends previous models by considering inhibition or stimulation of production of the response variable dependent on the amount of precursor which may accumulate or deplete after administration of some drugs. Standardized pharmacokinetic and pharmacodynamic parameters were used for generating dose, plasma concentration, and response-time profiles using computer simulations. The peak response (Rmax) and the time of its occurrence (TRmax) were dependent on the dose, degree of maximum inhibition (Imax) or stimulation (Smax), and drug concentrations causing 50% inhibition (IC50) or stimulation (SC50). The maximum rebound (RBmax) and the time of its occurrence (TRBmax) after a single bolus dose were also dependent on these factors, but were of lesser magnitude and showed relatively later occurrence. Interestingly, values of area between the baseline and effect curve (ABEC) and area between the baseline and rebound curve (ABRC) were equal for each set of conditions for each model, but the latter is reduced when there is a second pathway for loss of precursor. Tolerance occurs because of diverse mechanisms, and the response patterns demonstrated may be helpful in describing tolerance and rebound phenomena for drugs which affect precursor pools.

Nonlinear perpendicular least-squares regression in pharmacodynamics.

Currently available software for nonlinear regression does not account for errors in both the independent and the dependent variables. In pharmacodynamics, measurement errors are involved in the drug concentrations as well as in the effects. Instead of minimizing the sum of squared vertical errors (OLS), a Fortran program was written to find the closest distance from a measured data point to the tangent line of an estimated nonlinear curve and to minimize the sum of squared perpendicular distances (PLS). A Monte Carlo simulation was conducted with the sigmoidal Emax model to compare the OLS and PLS methods. The area between the true pharmacodynamic relationship and the fitted curve was compared as a measure of goodness of fit. The PLS demonstrated an improvement over the OLS by 20.8% with small differences in the parameter estimates when the random noise level had a standard deviation of five for both concentration and effect. Consideration of errors in both concentrations and effects with the PLS could lead to a more rational estimation of pharmacodynamic parameters.

Computer simulation of the effects of alterations in blood flows and body composition on thiopental pharmacokinetics in humans.

BACKGROUND: Understanding the influence of physiological variables on thiopental pharmacokinetics would enhance the scientific basis for the clinical usage of this anesthetic. METHODS: A physiological pharmacokinetic model for thiopental previously developed in rats was scaled to humans by substituting human values for tissue blood flows, tissue masses, and elimination clearance in place of respective rat values. The model was validated with published serum concentration data from 64 subjects. The model was simulated after intravenous thiopental administration, 250 mg, over 1 min, to predict arterial plasma concentrations under conditions of different cardiac outputs, degrees of obesity, gender, or age. RESULTS: The human pharmacokinetic model is characterized by a steady state volume of distribution of 2.2 l/kg, an elimination clearance of 0.22 l/min, and a terminal half-life of 9 h. Measured thiopental concentrations are predicted with an accuracy of 6 +/- 37% (SD). Greater peak arterial concentrations are predicted in subjects with a low versus a high cardiac output (3.1 and 9.4 l/min), and in subjects who are lean versus obese (56 and 135 kg). Acutely, obesity influences concentrations because it affects cardiac output. Prolonged changes are due to differences in fat mass. Changes with gender and age are relatively minor. CONCLUSIONS: The physiological pharmacokinetic model developed in rats predicts thiopental pharmacokinetics in humans. Differences in basal cardiac output may explain much of the variability in early thiopental disposition between subjects.

No effect of age on the dose requirement of thiopental in the rat.

With increasing human age (20-80 years), the electroencephalogram (EEG) dose requirement for the intravenous anesthetic thiopental decreases approximately 10% per decade of life. The goal of this study was to compare the dose required to attain isoelectric EEG in young (4-5 month) vs. aged (24-25-month) Fischer 344 rats. One second isoelectricity was found to be an endpoint where minimal cardiorespiratory depression occurred. The effects of age, infusion rate, and repeated administration were examined in nine young and nine old rodents. Thiopental dose requirement increased with increasing infusion rates. Repeated administration at two-day intervals did not demonstrate tolerance to thiopental. No difference in thiopental dose requirement was detected in the young vs. elderly rats. In a separate group of five young and five old rats, thiopental plasma, brain, heart, and CSF concentrations were measured when five seconds of EEG isoelectricity was achieved: no consistent differences were noted. The rat may not be an appropriate model to investigate acute age-related anesthetic effects in humans, because cardiovascular changes with age are dissimilar between species.

Concentration-EEG effect relationship of propofol in rats.

Propofol is a unique highly lipid-soluble anesthetic that is formulated in a fat emulsion (Diprivan) for intravenous (i.v.) use. It has the desirable properties of rapid onset and offset of effect following rapid i.v. administration and minimal accumulation on long-term administration. Based on physicochemical properties and preliminary brain solubility data, propofol should have an extended effect-site turnover and a resulting prolonged effect. However, a preliminary study in humans has reported a rapid blood-brain equilibration half-time (T1/2 kE0) of only 2.9 min. We used a chronically instrumented rat model to examine the unique disposition and electroencephalographic (EEG) pharmacodynamics of propofol. Although the pharmacokinetics were variable, there was low interindividual variability in the concentration-EEG effect relationship. The duration of EEG sleep was 26 (+/- 44% CV) min following 11-15 mg/kg doses of propofol. The T1/2 kE0 was 1.7 (+/- 32%) min. Apparent effect-site concentrations of 0.5-1 microg/mL were required to maintain sleep in rats. Like other general anesthetics, the concentration-EEG effect relationship of propofol is biphasic. At a propofol concentration of 0.6 (+/- 35%) microg/mL, the number of EEG waves/s was maximal at 175% of baseline awake state. Further increases in the concentration of propofol depressed EEG activity until complete suppression occurred at 7 (+/- 22%) microg/mL.

Parameter estimability of biphasic response models.

Pharmacodynamics of general anesthetic agents generally exhibit biphasic concentration-effect relationships (i.e., an activation phase at low concentrations and inhibition at higher concentrations). These relationships are usually characterized with biphasic models constructed from various combinations and modifications of the nonlinear sigmoid E(MAX) model. We tested and quantified the parameter estimability of the simplest additive biphasic pharmacodynamic models by a Monte Carlo method. The estimated model parameters were used to calculate descriptors of the concentration-effect data. Parameters and descriptors were compared with their true values. When the IC50/EC50 ratio was low (<10), E(MAX), EC50, and IC50 were poorly estimated (high coefficient of variation and pronounced bias). However, the fit to the data was excellent, and the data descriptors calculated from the estimated model parameters demonstrated high precision and accuracy. Baseline effect (E0) was estimated with good precision and accuracy. As the IC50/EC50 ratio was increased, the estimability of model parameters and data descriptors improved, with the data descriptors continuing to be more estimable than model parameters. Thus, model parameters become estimable when there is sufficient separation between EC50 and IC50 to produce a plateauing of peak effect (activation), which can be observed directly from the data signature. Data descriptors are not subject to this limitation and thus may serve as better metrics for summarizing concentration-effect relationships.

Emulsion formulation reduces propofol's dose requirements and enhances safety.

BACKGROUND: Propofol, a highly lipophilic anesthetic, is formulated in a lipid emulsion for intravenous use. Propofol has brisk onset and offset of effect after rapid administration and retains rapid offset characteristics after long-term administration. The authors tried to determine whether the emulsion vehicle is requisite for propofol's evanescent effect-time profile. METHODS: The time course of sedation and electroencephalographic (EEG) effect after propofol administration was measured in three studies in rats instrumented. In study 1, propofol was infused in either emulsion or lipid-free vehicle (n = 12), in a repeated measures cross-over design. In study 2, propofol in lipid-free vehicle was infused with or without simultaneous infusion of drug-free lipid emulsion (n = 6) in a repeated measures cross-over design. In study 3, propofol was infused in either emulsion (n = 5) or lipid-free vehicle (n = 5) to EEG burst suppression. RESULTS: In study 1, relative to the emulsion formulation, propofol administered at equivalent doses in lipid-free vehicle resulted in a longer time to effect onset (1.4 +/- 0.2 vs. 0.5 +/- 0.1 min, EEG) and a trend for delayed anesthetic recovery (26.8 +/- 9.4 vs. 17 +/- 3.5 min, EEG; 26.1 +/- 8.8 vs. 16.8 +/- 3.3 min, sleep). In study 2, coadministration of drug-free emulsion with propofol did not alter the time course of effect. In study 3, more than twice the dose of propofol was required to achieve EEG burst suppression with the lipid-free formulation. Two animals died after administration of propofol to EEG burst suppression with the lipid-free formulation; no deaths occurred in the emulsion group. CONCLUSION: The incorporation of propofol in emulsion reduces dose requirements and produces rapid onset and recovery of anesthetic effect.

Feasibility of effect-controlled clinical trials of drugs with pharmacodynamic hysteresis using sparse data.

PURPOSE: To explore, by simulation procedures, the feasibility of characterizing, from sparse data, the concentration-effect relationship of drugs with pharmacodynamic hysteresis. METHODS: For computer simulations, the concentration-effect relationship was assumed to be describable by the Sigmoid-Emax equation, the site of drug action was located in a distinct effect compartment (keo = 10 x kelim), and the pharmacokinetics were those of either a linear one- or two-compartment system. In view of the poor estimability of the parameters of the Sigmoid-Emax model under the usual clinical conditions, central compartment post-distributive drug concentrations required to elicit various intensities of effect within the therapeutic range were used as data descriptors. Effect intensities of 5 and 25, or 25 and 50 units (with the "unknown" Emax = 100 units) were targeted in multiple-dose (steady state) trial designs. From these data, drug concentrations required to produce effect intensities of 15 and 50 units were estimated by both log-linear and linear interpolation and the actual effect intensities produced by these concentrations were calculated. These simulations were performed over a wide range of Hill coefficient values (0.5 to 4.0) and dosing intervals (0.1 to 1.5 x elimination t1/2. RESULTS: Acceptable results could be obtained by measuring drug concentrations and effect intensities at or near the end of a dosing interval. The largest deviations of effective concentration estimates (in terms of effect intensity) occurred at a Hill coefficient value of 0.5 and the results were very little affected by changing the dosing interval. CONCLUSIONS: Our results demonstrate that effect-controlled clinical trials, with sparse data, of drugs with pharmacodynamic hysteresis for determining concentration-effect relationship in the therapeutic range are feasible in principle.

High-performance liquid chromatographic assay of propofol in human and rat plasma and fourteen rat tissues using electrochemical detection.

This paper describes a sensitive HPLC-electrochemical detection analytical method for determining the concentration of the intravenous anesthetic, propofol, in human or rat plasma or serum and a variety of rat tissues. Internal standard and drug are extracted from serum or plasma and other tissues with pentane. 2,6-tert.-Butylmethylphenol is used as internal standard. It includes a novel steam distillation procedure for separating the highly lipophilic propofol from skin and fat. The plasma/serum assay has a precision of 1-4% (C.V.) in the range 10 ng/ml to 1 microgram/ml and permits the assay of assay of 5 ng/ml from 0.1 ml of plasma/serum. The tissue procedure allows the estimation of 50 ng/g in 0.1 g of tissue for most of the major organs with less than 2% (C.V.) precision. This assay was used to measure propofol concentrations in plasma/serum and tissue samples in support of a project to develop a physiological pharmacokinetic model for propofol in the rat.

Is it possible to estimate the parameters of the sigmoid Emax model with truncated data typical of clinical studies?

Many drug concentration-effect relationships are described by the nonlinear sigmoid E(max) model. Clinical considerations frequently limit the magnitude of effect intensity that may be produced; the most pronounced effect intensity may be considerably below E(max). We have tested and quantified the influence of this limitation on the estimatability of the sigmoid E(max) model parameters. We have used the estimated parameter values to calculate data descriptors (drug concentrations required to produce certain effect intensities) and compared these with concentrations determined by using exact parameter values. We found that when the highest measured effect intensity was less than 95% of E(max), E(max) and EC50 were poorly estimated (high coefficient of variation and pronounced bias). Nevertheless, the fit to the data was quite good and the data descriptors were estimated with precision within the range for which data were available but not beyond. Baseline effect was estimated with good precision but the sigmoidicity parameter (gamma) was highly variable. Thus, where clinical considerations prevent determination of concentration-effect data near the maximum effect intensity, E(max) and EC50 estimations are unreliable. The use of estimable data descriptors is proposed to characterize the concentration-effect relationship under these conditions.

Quantitation of depth of thiopental anesthesia in the rat.

BACKGROUND: In contrast to that of inhalational anesthetics, quantitation of anesthetic depth for intravenous agents has not been well defined. In this study, using rodents, the relationship between the constant plasma thiopental concentrations and the clinical response to multiple nociceptive stimuli were investigated characterizing the anesthetic state from light sedation to deep anesthesia and correlated to the degree of electroencephalogram (EEG) drug effect. METHODS: Thirty rats were instrumented with chronically implanted EEG electrodes, arterial and venous catheters. A computer-driven infusion pump was used to rapidly attain and then maintain constant, target plasma thiopental concentrations ranging from 7 to 100 micrograms/ml. Three different target plasma thiopental concentrations were achieved in each rat. Electroencephalographic effects were monitored with aperiodic waveform analysis. The following nociceptive stimuli were applied: (1) unprovoked righting reflex, (2) provoked righting reflex, (3) noise stimulus, (4) tail clamping with an alligator clip, (5) constant tail pressure with an analgesiameter, (6) corneal reflex, and (7) tracheal intubation. For tail clamping, tail pressure, and intubation, either purposeful extremity movement or abdominal muscle contraction response was noted to be present or absent. The clinical responses (present or absent) were modeled using logistic regression to estimate the Cp50, the plasma thiopental concentration with a 50% probability of no response. RESULTS: The following mean Cp50 values (95% confidence interval) were obtained: unprovoked righting reflex, 15.9 (15.1-16.6) micrograms/ml; provoked righting reflex, 21.4 (20.2-22.7) micrograms/ml; noise stimuli, 31.3 (29.7-33.0) micrograms/ml; tail clamp and limb movement, 38.3 (36.1-40.4) micrograms/ml; tail pressure and limb movement, 39.2 (37.1-41.3) micrograms/ml; tail pressure and abdominal muscle contraction, 52.5 (50.0- 55) micrograms/ml; tail clamping and abdominal muscle contraction, 56.1 (50.0-56.2) micrograms/ml; corneal reflex, 60.0 (56.6-63.4) micrograms/ml; and limb movement or muscle abdominal contraction response to intubation, 67.7 (59.2-76.1) micrograms/ml. At an EEG-effect of 9.1 and 2.2 waves/s, there was a 50% chance of limb movement response to tail clamping and tracheal intubation, respectively. There was a poor relationship between the plasma thiopental concentration and the percent increase of either heart rate or mean arterial blood pressure after applying either tail pressure or tail clamp stimuli. CONCLUSIONS: A range of nociceptive stimuli and their observed clinical responses can be used to quantitate thiopental anesthetic depth, ranging from light sedation to deep anesthesia (isoelectric EEG and unresponsive to intubation) in the rodent. Clinical response can be mapped to surrogate EEG measures.

Population pharmacodynamics: strategies for concentration-and effect-controlled clinical trials.

OBJECTIVE: To explore and evaluate various strategies for drug concentration-and effect-controlled clinical trials, respectively, in the context of studies of population pharmacodynamics (concentration-effect relationships). METHODS: The relative utility of drug concentration- and pharmacologic effect-controlled, randomized clinical trials with two or three concentration-effect measurements for each subject has been explored by computer simulation. The basis for these simulations was a sigmoid-Emax (maximum effect) pharmacodynamic model with Emax = 100%, EC50 (drug concentrations required to produce an effective intensity of 50%) = 10 concentration units, gamma = 2, and no hysteresis. Emax and gamma were held constant whereas EC50 was assumed to be log-normally distributed with a 26% coefficient of variation of the natural lognormalized data. A smaller random variability and variability due to measurement error also were incorporated in the simulations. To explore the implications of variable and unknown Emax and gamma values, the suitability of linear and log-linear interpolation procedures for two-point concentration-effect data in different regions of the sigmoid-Emax curve was compared. RESULTS: Pharmacologic effect-controlled clinical trials with 300 hypothetical subjects and targeted effect intensities of 25% and 75% yielded very good estimates of drug concentrations required to produce effect intensities of 35%, 50%, and 65%, whereas concentration-controlled trials yielded much poorer estimates. Moreover, the concentration-controlled trials, despite optimum choice of targeted concentrations, yielded a large number of data points with poor information content (effect intensities of < 15% or > 85%). Determinations based on targeted effect intensities of 25% and 75% yielded better estimates of individual EC50 values than those targeted for 25% and 50% or 50% and 75% effect intensity. Results were not significantly improved by adding a third measurement (targeted to 50% effect) to the 25% and 75% effect design. Estimations of drug concentrations required to produce an effect intensity of 50%, based on log-linear interpolation of exact concentration-effect data at 25% and 75%, yielded exact results independent of gamma value (0.5-8.0) whereas linear interpolation produced large overestimates at gamma = 0.5 or 1.0 but satisfactory estimates at gamma > or = 2.0. Similar calculations for an effect intensity of 15% based on exact concentration-effect data at 5% and 25% yielded reasonably good estimates by both methods of interpolation over a wide range of gamma values. A review of the clinical literature showed that gamma values are usually 2 or higher. CONCLUSIONS: Population pharmacodynamic studies of reversibly acting drugs without pharmacodynamic hysteresis or time dependency (e.g., tolerance) can be successfully conducted using a pharmacologic effect-controlled randomized clinical trial design with only two properly selected target effect intensities per subject.

A PC-based graphical simulator for physiological pharmacokinetic models.

Since many intravenous anesthetic drugs alter blood flows, physiologically-based pharmacokinetic models describing drug disposition may be time-varying. Using the commercially available programming software MATLAB, a platform to simulate time-varying physiological pharmacokinetic models was developed. The platform is based upon a library of pharmacokinetic blocks which mimic physiological structure. The blocks can be linked together flexibly to form models for different drugs. Because of MATLAB's additional numerical capabilities (e.g. non-linear optimization), the platform provides a complete graphical microcomputer-based tool for physiologic pharmacokinetic modeling.

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 wholebody 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.