基于PBPK建模预测替格瑞洛在人体内的药动学行为

目的:建立替格瑞洛在健康人群中的生理药动学(PBPK)模型,预测其口服给药后在人体的吸收部位与吸收量及组织分布特征,为预测替格瑞洛药物互相作用和临床治疗提供参考依据。方法:通过文献和ADMET Predictor软件计算获取替格瑞洛建模的理化参数及生物药剂学参数,通过替格瑞洛注射给药的药动学数据获取替格瑞洛在人体的清除率(CL),应用Gastro PlusTM软件建立替格瑞洛口服给药的PBPK预测模型,并对模型进行验证和优化。通过所建立的预测模型,能预测药物体内药-时曲线,预测药物吸收部位与吸收量及口服给药后药物在各个组织及器官中的药物暴露量。结果:模型拟合替格瑞洛的药-时曲线与实测值的平均折合误差(AFE)和绝对平均折合误差(AAFE)值分别为1.0和1.1,这表明所建立的PBPK模型有效性良好。药物主要的吸收部位为空肠,吸收量为35.8%。口服替格瑞洛后,药物在身体各个组织中均有广泛的分布,其在脂肪组织、红骨髓和黄骨髓中的药物显露量约是血中药物暴露量1.6倍。结论:所建立的PBPK模型可较好模拟替格瑞洛口服给药后的体内药动学行为,对于预测药物可能的相互作用及临床给药方案有指导意义。     

Development and application of a physiologically based pharmacokinetic model for triadimefon and its metabolite triadimenol in rats and humans

A physiologically based pharmacokinetic (PBPK) model was developed for the conazole fungicide triadimefon and its primary metabolite, triadimenol. Rat tissue:blood partition coefficients and metabolic constants were measured in vitro for both compounds. Pharmacokinetic data for parent and metabolite were collected from several tissues after intravenous administration of triadimefon to male Sprague-Dawley rats. The model adequately simulated peak blood and tissue concentrations but predicted more rapid clearance of both triadimefon and triadimenol from blood and tissues. Reverse metabolism of triadimenol to triadimefon in the liver was explored as a possible explanation of this slow clearance, with significant improvement in model prediction. The amended model was extrapolated to humans using in vitro metabolic constants measured in human hepatic microsomes. Human equivalent doses (HEDs) were calculated for a rat no observable adverse effect level (NOAEL) dose of 3.4 mg/kg/day using area under the concentration curve (AUC) in brain and blood for triadimefon and triadimenol as dosimetrics. All dosimetric-based HEDs were 25-30 fold above the human oral reference dose of 0.03 mg triadimefon/kg/day, but did not account for intra-human variability or pharmacodynamic differences. Ultimately, derivations of this model will be able to better predict the exposure profile of these and other conazole fungicides in humans.     

Prediction of the volumes of distribution of basic drugs in humans based on data from animals

The apparent volume of distribution-after distribution equilibrium and the ratio of distributive tissue volume to the unbound fraction in the tissue (V_T/fu_T)of 10 weak basic drugs, i.e., chlorpromazine, imipramine, propranolol, disopyramide, lidocaine, quinidine, meperidine, pentazocine, chlorpheniramine, and methacyclin were compared in animal species and humans. In these two parameters, a statistically significant correlation between animals and humans was obtained, when the parameters were plotted on a log-log scale. The correlation coefficient between V_T/fu_T was significantly higher than that between the apparent volumes of distribution (p<0.05). In general, there was little difference between V_T/fu_T of various basic drugs in animals and that in humans. Prediction of the apparent volume of distribution in humans using animal data of V_T/fu_T,plasma unbound fraction, blood volume, and blood-to-plasma concentration ratio in humans was successful for most of drugs studied.     

Estimated cancer risk of dioxins to humans using a bioassay and physiologically based pharmacokinetic model

The health risk of dioxins and dioxin-like compounds to humans was analyzed quantitatively using experimental data and mathematical models. To quantify the toxicity of a mixture of three dioxin congeners, we calculated the new relative potencies (REPs) for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), and 2,3,4,7,8- pentachlorodibenzofuran (PeCDF), focusing on their tumor promotion activity. We applied a liver foci formation assay to female SD rats after repeated oral administration of dioxins. The REP of dioxin for a rat was determined using dioxin concentration and the number of the foci in rat liver. A physiologically based pharmacokinetic model (PBPK model) was used for interspecies extrapolation targeting on dioxin concentration in liver. Toxic dose for human was determined by back-estimation with a human PBPK model, assuming that the same concentration in the target tissue may cause the same level of effect in rats and humans, and the REP for human was determined by the toxic dose obtained. The calculated REPs for TCDD, PeCDD, and PeCDF were 1.0, 0.34, and 0.05 for rats, respectively, and the REPs for humans were almost the same as those for rats. These values were different from the toxic equivalency factors (TEFs) presented previously (Van den Berg, M., Birnbaum, L., Bosveld, A.T.C., Brunstrom, B., Cook, P., Feeley, M., Giesy, J.P., Hanberg, A., Hasegawa, R., Kennedy, S.W., Kubiak, T., Larsen, J.C., Rolaf van Leeuwen, F.X., Liem, A.K.D., Nolt, C., Peterson, R.E., Poellinger. L., Safe, S., Schrenk, D., Tillitt, D, Tysklind, M., Younes, M., Waern, F., Zacharewski, T., 1998. Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environ. Health Perspect. 106, 775-792). The relative risk of excess liver cancer for Japanese people in general was 1.7-6.5 x 10(-7) by TCDD only, and 2.9-11 x 10(-7) by the three dioxins at the present level of contamination.     

Prediction of aztreonam pharmacokinetics in humans based on data from animals

Interspecies correlations of pharmacokinetic parameters obtained in animals were used to predict human pharmacokinetics in order to design the first clinical study of an investigational drug. The serum pharmacokinetics of aztreonam, a novel monocyclic beta-lactam antibiotic, were described for mice, rats, rabbits, and monkeys, using serum clearance and apparent volume of distribution. A one-compartment pharmacokinetic model yielded predictions for aztreonam clinical pharmacokinetics that were very helpful in choosing doses and serum sampling times for the first kinetic study in healthy male volunteers. Predicted serum aztreonam concentrations agreed well with subsequently measured values in man.     

Development of a physiologically based pharmacokinetic model for ethylene glycol and its metabolite, glycolic Acid, in rats and humans.

An extensive database on the toxicity and modes of action of ethylene glycol (EG) has been developed over the past several decades. Although renal toxicity has long been recognized as a potential outcome, in recent years developmental toxicity, an effect observed only in rats and mice, has become the subject of extensive research and regulatory reviews to establish guidelines for human exposures. The developmental toxicity of EG has been attributed to the intermediate metabolite, glycolic acid (GA), which can become a major metabolite when EG is administered to rats and mice at high doses and dose rates. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to integrate the extensive mode of action and pharmacokinetic data on EG and GA for use in developmental risk assessments. The resulting PBPK model includes inhalation, oral, dermal, intravenous, and subcutaneous routes of administration. Metabolism of EG and GA were described in the liver with elimination via the kidneys. Metabolic rate constants and partition coefficients for EG and GA were estimated from in vitro studies. Other biochemical constants were optimized from appropriate in vivo pharmacokinetic studies. Several controlled rat and human metabolism studies were used to validate the resulting PBPK model. When internal dose surrogates were compared in rats and humans over a broad range of exposures, it was concluded that humans are unlikely to achieve blood levels of GA that have been associated with developmental toxicity in rats following occupational or environmental exposures.     

A physiologically based pharmacokinetic model for methyl tert-butyl ether in humans: implementing sensitivity and variability analyses.

Methyl tert-butyl ether (MTBE) is added to gasoline to reduce carbon monoxide and ozone precursors from automobile emissions. The objectives of this study were to verify the ability of a physiologically based pharmacokinetic (PBPK) model to predict MTBE blood levels in humans and to investigate the effect of variability in the metabolism of MTBE and its influence on the predicted MTBE blood levels. The model structure for MTBE was flow-limited and had six essential compartments: lung, liver, rapidly perfused tissues, slowly perfused tissues, fat, and kidney. In this model, two pathways of metabolism are described to occur in the liver by Michaelis-Menten kinetics. Metabolic rate constants were measured in vitro using human liver microsomes and extrapolated to in vivo whole-body metabolism. Model predictions were compared with data on blood levels of MTBE taken from humans during and after a 1-h inhalation exposure to 1.7 ppm MTBE and after 4-h inhalation exposures to 4 or 40 ppm MTBE. The PBPK model accurately predicted MTBE pharmacokinetics at the high and low MTBE exposure concentrations for all time points. At the intermediate MTBE exposure concentration, however, the model underpredicted early time points while adequately predicting later time points. Results of the sensitivity analysis indicated that the influence of metabolic parameters on model output was dependent on MTBE exposure concentration. Subsequent variability analysis indicated that there was more variability in the actual measured MTBE blood levels than in the blood levels predicted by the PBPK model when using the range of metabolic parameters measured in vitro in human liver samples. By incorporating an understanding of the metabolic processes, this PBPK model can be used to predict blood levels of MTBE, which is important in determining target tissue dose estimates for risk assessment.     

Blockade of central vasopressin receptors reduces the cardiovascular response to acute stress in freely moving rats

To investigate the contribution of central vasopressin receptors to blood pressure (BP) and heart rate (HR) response to stress we injected non-peptide selective V(1a) (SR49059), V(1b) (SSR149415), V(2) (SR121463) receptor antagonists, diazepam or vehicle in the lateral cerebral ventricle of conscious freely moving rats stressed by blowing air on their heads for 2 min. Cardiovascular effects of stress were evaluated by analyzing maximum increase of BP and HR (MAX), latency of maximum response (LAT), integral under BP and HR curve (integral), duration of their recovery and spectral parameters of BP and HR indicative of increased sympathetic outflow (LF(BP) and LF/HF(HR)). Moreover, the increase of serum corticosterone was measured. Exposure to air-jet stress induced simultaneous increase in BP and HR followed by gradual decline during recovery while LF(BP) oscillation remained increased as well as serum corticosterone level. Rats pre-treated with vasopressin receptor antagonists were not sedated while diazepam induced sedation that persisted during exposure to stress. V(1a), V(1b) and V(2) receptor antagonists applied separately did not modify basal values of cardiovascular parameters but prevented the increase in integral(BP). In addition, V(1b) and V(2) receptor antagonists reduced BP(MAX) whereas V(1a), V(1b) antagonist and diazepam reduced HR(MAX) induced by exposure to air-jet stress. All drugs shortened the recovery period, prevented the increase of LF(BP) without affecting the increase in serum corticosterone levels. Results indicate that vasopressin receptors located within the central nervous system mediate, in part, the cardiovascular response to air-jet stress without affecting either the neuroendocrine component or inducing sedation. They support the view that the V(1b) receptor antagonist may be of potential therapeutic value in reducing arterial pressure induced by stress-related disorders.     

Metabolism and physiologically based pharmacokinetic modeling of flumioxazin in pregnant animals

A physiologically based pharmacokinetic (PBPK) model was developed to predict the concentration of flumioxazin, in the blood and fetus of pregnant humans during a theoretical accidental intake (1000 mg/kg). The data on flumioxazin concentration in pregnant rats (30 mg/kg po) was used to develop the PBPK model in pregnant rats using physiological parameters and chemical specific parameters. The rat PBPK model developed was extrapolated to a human model. Liver microsomes of female rats and a mixed gender of humans were used for the in vitro metabolism study. To determine the % of flumioxazin absorbed after administration at a dose of 1000 mg/kg assuming maximum accidental intake, the biliary excretion study of [phenyl-U-¹⁴C]flumioxazin was conducted in bile duct-cannulated female rats (Crl:CD (SD)) to collect and analyze the bile, urine, feces, gastrointestinal tract, and residual carcass. The % of flumioxazin absorbed at a dose of 1000 mg/kg in rats was low (12.3%) by summing up ¹⁴C of the urine, bile, and residual carcass. The pregnant human model that was developed demonstrated that the maximum flumioxazin concentration in the blood and fetus of a pregnant human at a dose of 1000 mg/kg po was 0.86 μg/mL and 0.68 μg/mL, respectively, which is much lower than K_m (202.4 μg/mL). Because the metabolism was not saturated and the absorption rate was low at a dose of 1000 mg/kg, the calculated flumioxazin concentration in pregnant humans was thought to be relatively low, considering the flumioxazin concentration in pregnant rats at a dose of 30 mg/kg. For the safety assessment of flumioxazin, these results would be useful for further in vitro toxicology experiments.     

Development of a physiologically based pharmacokinetic (PBPK) model for methyl iodide in rats,rabbits, and humans

Methyl iodide (MeI) has been proposed as an alternative to methyl bromide as a pre-plant soil fumigant that does not deplete stratospheric ozone. In inhalation toxicity studies performed in animals as part of the registration process, three effects have been identified that warrant consideration in developing toxicity reference values for human risk assessment: nasal lesions (rat), acute neurotoxicity (rat), and fetal loss (rabbit). Uncertainties in the risk assessment can be reduced by using an internal measure of target tissue dose that is linked to the likely mode of action (MOA) for the toxicity of MeI, rather than the external exposure concentration. Physiologically based pharmacokinetic (PBPK) models have been developed for MeI and used to reduce uncertainties in the risk assessment extrapolations (e.g. interspecies, high to low dose, exposure scenario). PBPK model-derived human equivalent concentrations comparable to the animal study NOAELs (no observed adverse effect levels) for the endpoints of interest were developed for a 1-day, 24-hr exposure of bystanders or 8?hr/day exposure of workers. Variability analyses of the PBPK models support application of uncertainty factors (UF) of approximately 2 for intrahuman pharmacokinetic variability for the nasal effects and acute neurotoxicity.     

A physiologically based pharmacokinetics model for melatonin—Effects of light and routes of administration

Physiologically based pharmacokinetic (PBPK) models were developed using MATLAB Simulink^® to predict diurnal variations of endogenous melatonin with light as well as pharmacokinetics of exogenous melatonin via different routes of administration. The model was structured using whole body, including pineal and saliva compartments, and parameterized based on the literature values for endogenous melatonin. It was then optimized by including various intensities of light and various dosage and formulation of melatonin. The model predictions generally have a good fit with available experimental data as evaluated by mean squared errors and ratios between model-predicted and observed values considering large variations in melatonin secretion and pharmacokinetics as reported in the literature. It also demonstrates the capability and usefulness in simulating plasma and salivary concentrations of melatonin under different light conditions and the interaction of endogenous melatonin with the pharmacokinetics of exogenous melatonin. Given the mechanistic approach and programming flexibility of MATLAB Simulink^®, the PBPK model could provide predictions of endogenous melatonin rhythms and pharmacokinetic changes in response to environmental (light) and experimental (dosage and route of administration) conditions. Furthermore, the model may be used to optimize the combined treatment using light exposure and exogenous melatonin for maximal phase advances or delays.     

Assessment of the percutaneous absorption of trichloroethylene in rats and humans using MS/MS real-time breath analysis and physiologically based pharmacokinetic modeling.

The development and validation of noninvasive techniques for estimating the dermal bioavailability of solvents in contaminated soil and water can facilitate the overall understanding of human health risk. To assess the dermal bioavailability of trichloroethylene (TCE), exhaled breath was monitored in real time using an ion trap mass spectrometer (MS/MS) to track the uptake and elimination of TCE from dermal exposures in rats and humans. A physiologically based pharmacokinetic (PBPK) model was used to estimate total bioavailability. Male F344 rats were exposed to TCE in water or soil under occluded or nonoccluded conditions by applying a patch to a clipper-shaved area of the back. Rats were placed in off-gassing chambers and chamber air TCE concentration was quantified for 3-5 h postdosing using the MS/MS. Human volunteers were exposed either by whole-hand immersion or by attaching patches containing TCE in soil or water on each forearm. Volunteers were provided breathing air via a face mask to eliminate inhalation exposure, and exhaled breath was analyzed using the MS/MS. The total TCE absorbed and the dermal permeability coefficient (K(P)) were estimated for each individual by optimization of the PBPK model to the exhaled breath data and the changing media and/or dermal patch concentrations. Rat skin was significantly more permeable than human skin. Estimates for K(P) in a water matrix were 0.31 +/- 0.01 cm/h and 0.015 +/- 0.003 cm/h in rats and humans, respectively. K(P) estimates were more than three times higher from water than soil matrices in both species. K(P) values calculated using the standard Fick's Law equation were strongly affected by exposure length and volatilization of TCE. In comparison, K(P) values estimated using noninvasive real-time breath analysis coupled with the PBPK model were consistent, regardless of volatilization, exposure concentration, or duration.     

Opportunities and challenges of physiologically based pharmacokinetic modeling in drug delivery

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Testosterone hydroxylation in bovine liver: enzyme kinetic and inhibition study

1. In order to sort out the involvement of cytochrome P450 (CYP) 3A and possibly CYP2B in testosterone hydroxylation in cattle, enzyme kinetic and inhibition studies were performed.

2. Most relevant kinetic constants (Km and Vmax) for 6β-, 16β- and 2β-testosterone hydroxylase (OHT) activities were determined and accounted for 93.4?±?13.8, 36.4?±?6.1 and 110.8?±?15.2?μM, respectively, for Km and 0.558?±?0.03, 0.280?±?0.013, and 0.338?±?0.017?nmol min–1 mg–1 protein, respectively, for Vmax. Eadie–Hofstee plot analysis pointed out how these enzymatic activities in cattle follow a monophasic kinetic pattern.

3. Preliminary inhibition studies conducted with the CYP3A inhibitor ketoconazole and the CYP2B inhibitors orphenadrine and 9-ethynylphenanthrene seemed to suggest the major involvement of CYP3A in testosterone hydroxylation in cattle.

4. Immuno-inhibition studies with an anti-peptide antibody against bovine CYP3A4 confirmed the predominant role of CYP3A in testosterone hydroxylation in bovine liver, proving the usefulness of anti-peptide antibodies in defining the contribution of specific P450 isoforms in drug metabolism in veterinary species.

     

Development of a physiologically based pharmacokinetic model of diisononyl phthalate (DiNP) in pregnant rat and human

ABSTRACT

A physiologically based pharmacokinetic (PBPK) model for di-isononyl phthalate (DiNP) was developed by adapting the existing models for di(2-ethylhexyl) phthalate (DEHP) and di-butylphthalate (DBP). Both pregnant rat and human time-course plasma and urine data were used to address the hydrolysis of DiNP in intestinal tract, plasma, and liver as well as hepatic oxidative metabolism and conjugation of the monoester and primary oxidative metabolites. Data in both rats and humans were available to inform the uptake and disposition of mono-isononyl phthalate (MiNP) as well as the three primary oxidative metabolites including hydroxy (7-OH)-, oxo (7-OXO)-, and carboxy (7-COX)-monoisononyl phthalate in plasma and urine. The DiNP model was reliable over a wide range of exposure levels in the pregnant rat as well as the two low exposure levels in humans including capturing the nonlinear behavior in the pregnant rat after repeated 750 mg/kg/day dosing. The presented DiNP PBPK model in pregnant rat and human, based upon an extensive kinetic dataset in both species, may provide a basis for assessing human equivalent exposures based upon either rodent or in vitro points of departure.     

The use of in vitro metabolic parameters and physiologically based pharmacokinetic (PBPK) modeling to explore the risk assessment of trichloroethylene

A physiologically based pharmacokinetic (PBPK) model has been developed for trichloroethylene (1,1,2-trichloroethene, TRI) for rat and humans, based on in vitro metabolic parameters. These were obtained using individual cytochrome P450 and glutathione S-transferase enzymes. The main enzymes involved both for rats and humans are CYP2E1 and the μ- and π-class glutathione S-transferases. Validation experiments were performed in order to test the predictive value of the enzyme kinetic parameters to describe ‘whole-body’ disposition. Male Wistar rats were dosed orally or intravenously with different doses of trichloroethylene. Obtained exhaled radioactivity, excreted radioactivity in urine, and obtained blood concentration–time curves of trichloroethylene for all dosing groups were compared to predictions from the PBPK model. Subsequently, using the scaling factor derived from the rat experiments predictions were made for the extreme cases to be expected in humans, based on interindividual variations of the key enzymes involved. On comparing these predictions with literature data a very close match was found. This illustrates the potential application of in vitro metabolic parameters in risk assessment, through the use of PBPK modeling as a tool to understand and predict in vivo data. From a hypothetical 8 h exposure scenario to 35 ppm trichloroethylene in rats and humans, and assuming that the glutathione S-transferase pathway is responsible for the toxicity of trichloroethylene, it was concluded that humans are less sensitive for trichloroethylene toxicity than rats.     

Development of a physiologically based pharmacokinetic model for estradiol in rats and humans: a biologically motivated quantitative framework for evaluating responses to estradiol and other endocrine-active compounds.

A physiologically based pharmacokinetic (PBPK) model for estradiol (E2) in rats and humans (male and female) was developed to provide a quantitative tool for evaluating the importance of physiological parameters on E2 blood and tissue concentration time-course and for predicting blood and tissue concentrations in rats and humans. A hepatic extraction model was developed to evaluate the significance of plasma protein binding on the hepatic extraction of E2 and the approach was integrated into the E2 model. Sufficient data was available to parameterize and validate oral and iv routes. The E2 model simulations of E2 blood and tissue concentrations compared well to experimental values. Estrogen receptor content strongly impacts distribution and elimination kinetics of E2 as well as tissue concentrations. The prolonged terminal elimination phase seen after iv bolus administration reflects the slow release of receptor bound E2 from tissues. E2 uptake behavior in the ovariectomized, but not intact rat uterus, was best described as diffusion-limited. Simulations with the hepatic extraction model predicted extensive binding of E2 to albumin (rat) and SHBG (sex-hormone binding globulin humans), although hepatic extraction does not appear to be restricted to the unbound fraction, implying that the total plasma E2 concentration is important when considering hepatic uptake. Important determinants of E2 disposition are tissue ER content and binding affinity, nonreceptor binding proteins, vascular permeability, partition coefficients, hepatic blood flow, and extrahepatic metabolism. As an integral part of a research program, the quantitative framework developed for E2 can be extended to other endocrine-active compounds (EACs) and used to evaluate the biological activity of EACs.     

Prediction of volume of distribution at steady state in humans: comparison of different approaches

INTRODUCTION: Reasonable prediction of volume of distribution at steady state (Vd(ss)) in humans is required for screening drug candidates, evaluating drug safety, and estimating first-in-human doses. AREAS COVERED: This review summarizes methods for the prediction of human Vd(ss) and tissue plasma partition coefficients (K(p)). The methods reviewed includes allometric scaling, physiologically based models, correlation with animal Vd(ss) and in silico models. The assumptions, equations, input data required, advantages, and limitations of each approach are discussed. Due to the variations among test datasets, some studies have reached inconsistent conclusions. Hence, a comprehensive comparison of various approaches using a large and exhaustive dataset is warranted to address the controversies in human Vd(ss) prediction. EXPERT OPINION: Compared with allometric scaling, the Oie-Tozer method and correlations between human and animal Vd(ss) are more accurate. All the three methods can be used for accurate predictions of human Vd(ss) just prior to first-in-human studies. Although in vivo animal data are not required, tissue composition-based approaches and inter-tissue correlation of K(p) provide reasonable predictive accuracies and are promising for physiologically based pharmacokinetic modeling. The in silico models are most suitable for high-throughput screening of compounds, which are at an early stage of development.     

Initial volume of a drug before it reaches the volume of distribution: pharmacokinetics of F(ab')2 antivenoms and other drugs.

Fast disappearance of F(ab')2 antivenoms from the plasma compartment [Sevcik et al., 2004. Modelling Tityus scorpion venom and antivenom pharmacokinetics. Evidence of active immunoglobulin G's F(ab')2 extrusion mechanism from blood to tissues. Toxicon 44, 731-734; Vazquez et al., 2005. Pharmacokinetics of a F(ab')2 scorpion antivenom in healthy human volunteers. Toxicon 46, 797-805] suggests a quick time course to reach its final distribution volume. An equation was developed to describe how the volume occupied by a drug in the body grows with time. As discussed in the paper this equation is free of some shortcomings of an equation developed for the same purpose by Niazi [1976. Volume of distribution as a function of time. J. Pharm. Sci. 65, 452-454]. Fluorescence microscopy showed that the rapid initial decay in plasmatic F(ab')2 concentration may be related to uptake of F(ab')2 by vascular endothelium which, in combination with accumulation in the vascular wall connective tissue, may produce an intermediate plateau in F(ab')2 V(sl)(t), which reached its final value after 10 h. The V(sl)(t) equation predicts that the plasma concentration half-time of decay has little use to estimate how a drug distributes through the body to exert its action, and predicts that, in some instances, intermediate plateaus in the time course of V(sl)(t) exist. Data from the literature showed that the kinetic considerations for V(sl)(t) also apply to clevidipine, digoxin, digitoxin, lidocaine and thiopentone.