A compartmental model of hepatic disposition kinetics: 1. Model development and application to linear kinetics

The conventional convection–dispersion model is widely used to interrelate hepatic availability (F) and clearance (Cl) with the morphology and physiology of the liver and to predict effects such as changes in liver blood flow on F and Cl. The extension of this model to include nonlinear kinetics and zonal heterogeneity of the liver is not straightforward and requires numerical solution of partial differential equation, which is not available in standard nonlinear regression analysis software. In this paper, we describe an alternative compartmental model representation of hepatic disposition (including elimination). The model allows the use of standard software for data analysis and accurately describes the outflow concentration–time profile for a vascular marker after bolus injection into the liver. In an evaluation of a number of different compartmental models, the most accurate model required eight vascular compartments, two of them with back mixing. In addition, the model includes two adjacent secondary vascular compartments to describe the tail section of the concentration–time profile for a reference marker. The model has the added flexibility of being easy to modify to model various enzyme distributions and nonlinear elimination. Model predictions of F, MTT, CV², and concentration–time profile as well as parameter estimates for experimental data of an eliminated solute (palmitate) are comparable to those for the extended convection–dispersion model.     

Distribution in female rats of an anaesthetic intravenous dose of 14C-propofol.

1. Bolus i.v. doses of 14C-propofol (9 mg/kg) were administered to female rats for measurement of tissue levels of total 14C and propofol from 2 min to 24 h post-dose; whole-body autoradiography was studied at 6 min, 2 h and 24 h post-dose, and also involved 15-day pregnant rats. 2. The blood propofol concentration-time profile was fitted by a tri-exponential function corresponding to a three-compartment open model. Data show rapid distribution during the mixing period into highly perfused tissues and muscle, comprising the central compartment, and slower uptake into less well-perfused skin and adipose tissues comprising the deeper compartments. 3. The initial decline in blood propofol concentration was associated with redistribution (t1/2 4 min), the second decline (15-240 min post-dose) was associated with metabolism (t1/2 33 min) and the third decline reflected slow depletion of drug from deep tissue compartments (t1/2 6.4 h). 4. Blood and brain propofol concentrations on waking (at 7 min post-dose) were 4 micrograms/ml and 9 micrograms/g respectively; the model shows that, at this time, 30% of the dose was lost from the central compartment by redistribution and a similar amount by metabolism. 5. Tissue profiles of total 14C and propofol diverged for highly perfused tissues (other than brain) because of slow clearance of metabolites, accentuated by enterohepatic recirculation.     

Estimation of Intradermal Disposition Kinetics of Drugs: I. Analysis by Compartment Model with Contralateral Tissues

Purpose. The objectives of dermal application of drugs are not only systemic therapeutics, but also local ones. We would expect its intradermal kinetics to be dependent on its therapeutic purpose. To develop more efficient drugs for local or systemic therapeutics, it will be important to estimate quantitatively the intradermal disposition of drugs applied topically. We tried, therefore, to develop the compartment model to describe the intradermal disposition kinetics after topical application of drugs. Methods. In vivo percutaneous absorption study for antipyrine, a model compound, was performed using rats with tape-stripped skin, using the assumption that the stratum corneum permeability to drugs would be improved enough not to be a rate-limiting process. Results. To analyze the results obtained, a 4-compartment model, composed of donor cell, viable skin, muscle, and plasma compartments, was applied. Although the fitting lines obtained could describe the concentration-time profiles of antipyrine in each compartment very well, the concentration profiles in the contralateral tissues were extensively overestimated. Therefore, we developed a 6-compartment model which included the viable skin and muscle in the contralateral site, and analyzed the concentration-time curve of each compartment. The fitting curves were in good agreement with the experimental data for all the compartments including the contralateral viable skin and muscle, and thus, this model was recognized to be adequate for the estimation of intradermal kinetics after topical application. Judging from the obtained values of clearance from viable skin to plasma and from viable skin to muscle, about 80% of antipyrine penetrated into viable skin, which suggested it was absorbed into circulating blood and 20% was transported to muscle under viable skin. Conclusions. Pharmacokinetic analysis using the 6-compartment model would be very useful for the estimation of local and systemic availability after topical application of drugs.     

Cellular pharmacokinetics: effects of cytoplasmic diffusion and binding on organ transit time distribution

Distribution between well-stirred compartments is the classical paradigm in pharmacokinetics. Also in capillary-issue exchange modeling a barrier-limited approach is mostly adopted. As a consequence of tissue binding, however, drug distribution cannot be regarded as instantaneous even at the cellular level and the distribution process consists of at least two components: transmembrane exchange and cytoplasmic transport. Two concepts have been proposed for the cytoplasmic distribution process of hydrophobic or amphipathic molecules, (i) slowing of diffusion due to instantaneous binding to immobile cellular structures and (ii) slow binding after instantaneous distribution throughout the cytosol. The purpose of this study was to develop a general approach for comparing both models using a stochastic model of intra- and extravascular drug distribution. Criteria for model discrimination are developed using the first three central moments (mean, variance, and skewness) of the cellular residence time and organ transit time distribution, respectively. After matching the models for the relative dispersion the remaining differences in relative skewness are predicted, discussing the relative roles of membrane permeability, cellular binding and cytoplasmic transport. It is shown under which conditions the models are indistinguishable on the basis of venous organ outflow concentration-time curves. The relative dispersion of cellular residence times is introduced as a model-independent measure of cytoplasmic equilibration kinetics, which indicates whether diffusion through the cytoplasm is rate limiting. If differences in outflow curve shapes (their relative skewness) cannot be detected, independent information on binding and/or diffusion kinetics is necessary to avoid model misspecification. The method is applied to previously published hepatic outflow data of enalaprilat, triiodothyronine, and diclofenac. It provides a general framework for the modeling of cellular pharmacokinetics.     

Analysis of pethidine disposition in the pregnant rat by means of a physiological flow model

The disposition of pethidine (meperidine) in the pregnant rat is described by means of a physiological flow model. The model includes arterial and venous blood, brain, fat, fetal, hepatic, intestinal, muscular, pulmonar, and renal tissues. The concentration-time profiles of pethidine calculated by the model are consistent with experimental data, except for the brain and renal tissues, where the model predicts initially higher concentrations. Simulations are carried out to further explore the contribution from different organs on the kinetics in blood and tissues. The tissue-to-blood partition coefficients vary over a range from 5 to 316, where fat has the lowest and liver the highest after a correction is made due to hepatic extraction. Rapid uptake occurs into highly perfused organs such as brain, kidneys, liver, and lungs, followed by fetus, intestines, muscle, and fat. Data indicate no marked membrane resistance to pethidine of the investigated organs, except for fetal tissues, but rather a perfusion-limited uptake. Simulations suggest that muscles and adipose tissue play an important role in the rat, becoming the major reservoir of drug during the intermediate and terminal elimination phase, respectively. Volume of distribution and the biological half-life agree with reported findings. Pethidine is subject to a high systemic blood clearance, which exceeds the total hepatic blood flow in the rat. No degradation of pethidine is found in blood, and therefore a pulmonary expression for pethidine clearance is added as a potential source of pethidine elimination. The elimination of pethidine after a single i.v. bolus does is found to be dependent on simulated changes in cardiac output and hepatic blood flow. A simulation is performed with the scaled model to mimic the human concentration-time profiles in maternal blood and brain tissues and fetal tissue during repetitive doses of pethidine.     

Analysis of pethidine disposition in the pregnant rat by means of a physiological flow model

The disposition of pethidine (meperidine) in the pregnant rat is described by means of a physiological flow model. The model includes arterial and venous blood, brain, fat, fetal, hepatic, intestinal, muscular, pulmonar, and renal tissues. The concentration-time profiles of pethidine calculated by the model are consistent with experimental data, except for the brain and renal tissues, where the model predicts initially higher concentrations. Simulations are carried out to further explore the contribution from different organs on the kinetics in blood and tissues. The tissue-to-blood partition coefficients vary over a range from 5 to 316, where fat has the lowest and liver the highest after a correction is made due to hepatic extraction. Rapid uptake occurs into highly perfused organs such as brain, kidneys, liver, and lungs, followed by fetus, intestines, muscle, and fat. Data indicate no marked membrane resistance to pethidine of the investigated organs, except for fetal tissues, but rather a perfusion-limited uptake. Simulations suggest that muscles and adipose tissue play an important role in the rat, becoming the major reservoir of drug during the intermediate and terminal elimination phase, respectively. Volume of distribution and the biological half-life agree with reported findings. Pethidine is subject to a high systemic blood clearance, which exceeds the total hepatic blood flow in the rat. No degradation of pethidine is found in blood, and therefore a pulmonary expression for pethidine clearance is added as a potential source of pethidine elimination. The elimination of pethidine after a single i.v. bolus dose is found to be dependent on simulated changes in cardiac output and hepatic blood flow. A simulation is performed with the scaled model to mimic the human concentration-time profiles in maternal blood and brain tissues and fetal tissue during repetitive doses of pethidine.     

A minimal physiological model of thiopental distribution kinetics based on a multiple indicator approach.

Currently available models of thiopental disposition kinetics using only plasma concentration-time data neglect the influence of intratissue diffusion and provide no direct information on tissue partitioning in individual subjects. Our approach was based on a lumped-organ recirculatory model that has recently been applied to unbound compounds. The goal was to find the simplest model that accounts for the heterogeneity in tissue partition coefficients and accurately describes initial distribution kinetics of thiopental in dogs. To ensure identifiability of the underlying axially distributed capillary-tissue exchange model, simultaneously measured disposition data of the vascular indicator, indocyanine green, and the marker of whole body water, antipyrine, were analyzed together with those of thiopental. A model obtained by grouping the systemic organs in two subsystems containing fat and nonfat tissues, successfully described all data and allowed an accurate estimation of model parameters. The estimated tissue partition coefficients were in accordance with those measured in rats. Because of the effect of tissue binding, the diffusional equilibration time characterizing intratissue distribution of thiopental is longer than that of antipyrine. The approach could potentially be used in clinical pharmacokinetics and could increase our understanding of the effect of obesity on the disposition kinetics of lipid-soluble drugs.     

Physiologically based pharmacokinetics of cyclosporine A: reevaluation of dose-nonlinear kinetics in rats

The disposition kinetics of Cyclosporine A (CyA) in rat, based on measurement in arterial blood, appeared dose-linear over a wide i.v. dose range (1.2-30 mg/kg). Physiologically based pharmacokinetic (PBPK) analysis, however, demonstrated that this was an apparent observation resulting from counterbalancing nonlinear factors, such as saturable blood and tissue distribution, as well as clearance (CLb). A PBPK model was successfully developed taking into account these multiple nonlinear factors. Tissue distribution was distinctly different among various organs, being best described by either a linear model (muscle, fat; Model 1), one involving instantaneous saturation (lung, heart, bone, skin, thymus; Model 2), noninstantaneous saturation (kidney, spleen, liver, gut; Model 3), or one with saturable efflux (brain; Model 4). Overall, the whole body volume of distribution at steady state for unbound CyA (Vuss) decreased with increasing dose, due at least in part to saturation of tissue-cellular cyclophilin binding. Clearance, essentially hepatic, and described by the well-stirred model, was also adequately characterized by Michaelis-Menten kinetics, Km 0.60 microgram/ml. In model-based simulations, both volume of distribution at steady state (Vss,b) and CLb varied in a similar manner with dose, such that terminal t1/2 remained apparently unchanged; these dose responses were attenuated by saturable blood binding. CyA concentration measured in arterial blood was not always directly proportional to the true exposure, i.e., unbound or target tissue concentrations. The PBPK model not only described comprehensively such complicated PK relationships but also permitted assessment of the sensitivity of individual parameters to variation in local nonlinear kinetics. Using this approach, dose-dependent CyA uptake into brain was shown to be sensitive to both active and passive transport processes, and not merely the affinity of the active (efflux) transporter at the level of the blood-brain barrier.     

A Whole-Body Physiologically Based Pharmacokinetic Model Incorporating Dispersion Concepts: Short and Long Time Characteristics

In whole-body physiologically based pharmacokinetic (PBPK) models, each tissue or organ is frequently portrayed as a single well-mixed compartment with distribution, perfusion rate limited. However, single-pass profiles from isolated organ studies are more adequately described by models which display an intermediate degree of mixing. One such model is the dispersion model, which successfully describes the outflow profiles from the liver and the perfused hindlimb of many compounds, under a variety of conditions. A salient parameter of this model is the dispersion number, a dimensionless term, which characterizes the relative axial spreading of compound on transit through the organ. We have developed a whole-body PBPK model wherein the distribution of drug on transit through each organ is described by the dispersion model with closed boundary conditions incorporated. The model equations were numerically solved using finite differencing methods, in particular, the method of lines. An integrating routine suitable for solving stiff sets of equations was used. Physiological parameters, blood flows, and tissue volumes, were taken from the literature, as were the tissue dispersion numbers, which characterize the mixing properties of each tissue; where none could be found, the value was set as that for liver. On solution, tissue, venous and arterial blood concentration–time profiles are generated. The profiles exhibited both short and long time characteristics. Oscillations were observed in the venous and arterial profiles over the first 10 min of simulation for the rat. On scale-up to human, the effects were seen over a 30 min period. Longer time effects of tissue distribution involve buildup of drug in the large tissues of distribution: skeletal muscle, skin, and adipose. The extent of distribution in the large tissues was somewhat dependent on the magnitude of the dispersion number, the lower the dispersion number, the greater the extent of distribution after an intravenous bolus dose. The model has a distinct advantage over the well-stirred organ whole-body PBPK model in its ability to describe both short and long time characteristics.     

阿托伐他汀生理药动学模型的建立

目的:建立阿托伐他汀在健康人群中的生理药动学模型,预测其在人体内的组织分布及特征,为优化阿托伐他汀的治疗方案提供依据。方法:文献中获取关于阿托伐他汀理化参数及体外酶促动力学参数及数值。结合药物理化参数得到组织-血浆分配平衡系数(K_p),应用GastroPlus软件,建立阿托伐他汀的生理药动学模型, 验证模型有效性, 预测各器官组织中阿托伐他汀的经时变化,并运用模型预测阿托伐他汀在儿童及老年人群体内各器官组织中药物的经时变化,为个体化用药提供依据。结果:经验证,模型的有效性良好。阿托伐他汀在14个组织室均有分布,其中在血液、皮肤、肺中分布较高,C_max分别为6.04,1.70,1.32 ng·ml^-1;在脂肪和脑中分布较低,C_max分别为0.31,0.33 ng·ml^-1。儿童及老年人群体各器官组织阿托伐他汀的经时变化模型预测发现,儿童血液、皮肤、肺分布较高,C_max分别为12.49,3.52,2.73 ng·ml^-1;脑分布最低,C_max为0.69 ng·ml^-1;老年血液、皮肤、肺分布较高,C_max分别为8.97,2.53,1.96 ng·ml^-1;肌肉分布最低,C_max为0.63 ng·ml^-1。结论:儿童及老年体内阿托伐他汀不同组织分布的C_max为青年健康人群的两倍,显示年龄影响阿托伐他汀在体内的分布,儿童和老年人应用阿托伐他汀,存在较高发生不良反应的风险,应根据生理生化指标调整剂量,避免不良反应的发生。     

Oral bioavailability, tissue distribution and depletion of flumequine in the food producing animal, chicken for fattening.

Chickens were used to investigate kinetic properties including metabolism of flumequine after single IV and oral dose, and to study tissue depletion of flumequine after multiple oral doses. Plasma and tissue (muscle, kidney, liver and skin plus fat) concentrations of flumequine and its metabolite 7-hydroxyflumequine were determined using a HPLC method. After IV and oral administration (single-dose of 12 mg flumequine/kg bw), plasma concentration-time curves were best described by a two-compartment open model. Elimination half-life and mean residence time of flumequine in plasma were 6.91 and 5.90 h, respectively, after IV administration and 10.32 and 8.95 h after oral administration. Maximum plasma concentration was 3.62 microg/ml and interval from oral administration until maximum concentration was 1.43 h. Oral bioavailability was found to be 57%. Flumequine was converted to 7-hydroxyflumequine. After oral administration (24 mg/kg bw every 24 h for 5 days), renal and hepatic concentrations of flumequine (18-25 microg/kg) persisted for 4 days; however, at that time, flumequine residues were not detected in skin plus fat and muscle tissues. Flumequine administered at a dosage of 24 mg/kg bw every 24h for 5 days, with a withdrawal time of 2d ays, resulted in flumequine concentrations in target tissues that were less than the European Union maximal residue limits.     

Distribution in female rats of an anaesthetic intravenous dose of 14C-propofol

1. Bolus i.v. doses of ¹⁴C-propofol (9?mg/kg) were administered to female rats for measurement of tissue levels of total ¹⁴C and propofol from 2?min to 24?h post-dose; whole-body autoradiography was studied at 6?min, 2h and 24?h post-dose, and also involved 15-day pregnant rats.

2. The blood propofol concentration-time profile was fitted by a tri-exponential function corresponding to a three-compartment open model. Data show rapid distribution during the mixing period into highly perfused tissues and muscle, comprising the central compartment, and slower uptake into less well-perfused skin and adipose tissues comprising the deeper compartments.

3. The initial decline in blood propofol concentration was associated with redistribution (t_1/2 4?min), the second decline (15–240?min post-dose) was associated with metabolism (t_1/2 33?min) and the third decline reflected slow depletion of drug from deep tissue compartments (t_1/2 6.4h).

4. Blood and brain propofol concentrations on waking (at 7?min post-dose) were 4 μg/ml and 9 μg/g respectively; the model shows that, at this time, 30% of the dose was lost from the central compartment by redistribution and a similar amount by metabolism.

5. Tissue profiles of total ¹⁴C and propofol diverged for highly perfused tissues (other than brain) because of slow clearance of metabolites, accentuated by enterohepatic recirculation.     

头孢硫脒在大鼠生理药动学模型研究

目的 建立头孢硫脒在大鼠的生理药代动力学模型.方法 按照血流限速理论,采用Matlab系统构建生理药代动力学模型程序;模型包括血液、心脏、肺、肾脏、肝脏、肠、胃、脾、胰腺、骨骼肌、皮肤、脂肪和甲状腺等生理相关性组织.生理性模型参数归纳自文献,组织-血液平衡分配系数等药物相关系数由实验测定.结果 大鼠经脉给与头孢硫脒200mg/kg后,模型预测的药物浓度与试验观察值符合良好.结论 建立了头孢硫脒在大鼠的生理药代动力学模型.     

Model representation of salicylate pharmacokinetics using unbound plasma salicylate concentrations and metabolite urinary excretion rates following a single oral dose.

The pharmacokinetics of salicylic acid (SA) and its metabolites have been studied in 5 volunteers after administration of 3 g salicylic acid (as sodium salicylate) and collection of serial samples of blood and urine. SA and its metabolites were assayed with a HPLC method specific for each species. The urinary excretion rates of individual metabolites were analyzed using unbound plasma SA concentrations and Lineweaver-Burke plots. The analysis confirmed that the formation of SA urate (SU) and SA phenolic glucuronide (SPG) metabolites are saturable processes, and showed that the Michaelis-Menten values derived are consistent with earlier estimates derived solely from urinary data. The unbound salicylate plasma concentration-time profiles were then analyzed with various models assuming either saturable clearances for metabolite formation and/or saturable protein binding. The data were best described with a model that included both saturable protein binding and saturable metabolism. The model assumed first-order absorption kinetics and instantaneous distribution into extravascular and tissue compartments. The model was validated by comparing predicted relationships between the apparent volume of distribution, clearance, and plasma salicylate concentrations with previous relationships obtained using steady state data.     

Circulatory transport and capillary-tissue exchange as determinants of the distribution kinetics of inulin and antipyrine in dog

A pharmacokinetic model was developed to estimate physiologically meaningful parameters of distribution kinetics from plasma concentration-time data. The model is based on simultaneously measured disposition curves of drug and vascular marker. Employing residence time distribution theory, a recirculatory model with two subsystems, the pulmonary and systemic circulation, was constructed. In addition to intravascular mixing, the axially distributed model of the systemic circulation accounts for transcapillary transport of solutes, quantified by permeability-surface area product (PS) and diffusional equilibration time. Parameters of ICG, inulin, and antipyrine were estimated from disposition data obtained in awake dogs under control conditions and during an isoproterenol infusion or moderate hypovolemia. Results suggest that distribution kinetics is (1) governed by extravascular diffusion and (2) its dependency on cardiac output decreases with increasing diffusional resistance. Hemorrhage decreased the effective PS of inulin. In conclusion, this novel mechanistic model effectively described both the permeability-limited distribution of inulin into interstitial fluid and the flow-limited distribution of antipyrine into total body water and might be useful for other drugs.     

Structure-tissue distribution relationship based on physiological pharmacokinetics for NY-198, a new antimicrobial agent, and the related pyridonecarboxylic acids

Comparative physiological pharmacokinetic analysis has been carried out to elucidate the different tissue distribution characteristics among eight pyridonecarboxylic acids including newly developed NY-198. The urinary and fecal recoveries of NY-198 were 76.3 +/- 1.3% and 21.0 +/- 0.1% of the dose (mean +/- SE, N = 3), respectively, after the iv administration of [14C]NY-198 as a 20 mg/kg dose. Model-independent moment analysis of the serum concentration-time profile of [14C]NY-198 gave the volume of distribution at steady state per body weight (Vdss/BW) as 1150 ml/kg. Intrinsic renal clearance (CLint.kd) and intrinsic hepatic clearance (CLint.lv) were estimated to be 7.68 ml/min/kg and 6.33 ml/min/kg, respectively, by the cumulative urinary recovery and the area under the curve of the serum concentration-time profile of NY-198 and the blood flow rate. The tissue-to-serum partition coefficients (Kp) were determined from the analysis of the tissue and serum concentration-time profiles after iv bolus or infusion of nalidixic acid, NY-198, and its structural analogue NY-239. These values were also determined from the analysis of similar data reported in the literature for the other pyridonecarboxylic acids (enoxacin, miloxacin, ofloxacin, pefloxacin, and pipemidic acid). The Kp values of NY-198 ranged from 0.22 to 4.85 and were very similar to those for ofloxacin, being the highest in the disposing organs, kidneys and liver, the lowest in fat and brain, and modest in the other nondisposing organs. A good correlation (r = 0.981) was obtained between serum unbound fraction (fp) and the steady state distribution volume per body weight (Vd(ss)/BW), which was determined from the tissue partition coefficient. Additionally, comparatively good correlations were also obtained between fp and the Kp or apparent tissue-to-serum concentration ratio (Kp,app). Thus, the difference of serum unbound fraction has been demonstrated for the determining factor of the structure-dependent tissue distribution difference, whereas the tissue binding has been suggested to be only slightly different for respective tissues among PCA derivatives. The concentration-time profile for serum and tissues (lung, heart, muscle, kidney, liver, spleen, gut, bone, skin, and brain) was predicted for NY-198 by physiological pharmacokinetics using the averaged tissue-to-serum unbound concentration ratio (Kp,f) which was determined from the Kp,f of eight PCA analogues.(ABSTRACT TRUNCATED AT 400 WORDS)     

Physiologically based pharmacokinetic study on a cyclosporin derivative,SDZ IMM 125

The immunosuppressant, SDZ IMM 125 (IMM), is a derivative of cyclosporin A (CyA). The disposition kinetics of IMM in plasma, blood cells, and various tissues of the rat was characterized by a physiologically based pharmacokinetic (PBPK) model; the model was then applied to predict the disposition kinetics in dog and human. Accumulation of IMM in blood cell is high (equilibrium blood cell/plasma ratio=8), although the kinetics of drug transference between plasma and blood cell is moderately slow, taking approximately 10 min to reach equilibrium, implying a membranelimited distribution into blood cells. A local PBPK model, assuming blood-flow limited distribution and tissue/blood partition coefficient (K _P) data, failed to adequately describe the observed kinetics of distribution, which were slower than predicted. A membrane transport limitation is therefore needed to model dynamic tissue distribution data. Moreover, a slowly interacting intracellular pool was also necessary to adequately describe the kinetics of distribution in some organs. Three elimination pathways (metabolism, biliary secretion, and glomerular filtration) of IMM were assessed at steady statein vivo and characterized independently by the corresponding clearance terms. A whole-body PBPK model was developed according to these findings, which described closely the IMM concentration-time profiles in arterial blood as well as 14 organs/tissues of the rat after intravenous administration. The model was then scaled up to larger mammals by modifying physiological parameters, tissue distribution and elimination clearances;in vivo enzymatic activity was considered in the scale-up of metabolic clearance. The simulations agreed well with the experimental measurements in dog and human, despite the large interspecies difference in the metabolic clearance, which does not follow the usual allometric relationship. In addition, the nonlinear increase in maximum blood concentration andAUC with increasing dose, observed in healthy volunteers after intravenous administration, was accommodated quantitatively by incorporating the known saturation of specific binding of IMM to blood cells. Overall, the PBPK model provides a promising tool to quantitatively link preclinical and clinical data.     

A pharmacokinetic model for high-dose methotrexate infusions in man

The infusion of high doses of methotrexate followed by folinic acid rescue is clinically useful against a variety of tumors. We studied the plasma pharmacokinetics of high-dose methotrexate infusions in patients with advanced cancer and devised a compartmental, kinetic model. our model is based on an earlier, mathematical model which describes the pharmacokinetics of moderate- to- high-dose methotrexate given as a single, intravenous injection. Mathematical equations for our model were solved on a UNIVAC1108 computer with the SAAM program. Seven compartments represent the distribution spaces for methotrexate and its metabolites. The transport of drug into and out of compartments is described by first-order differential equations. A nonlinear, concentration-dependent function is used for renal excretion with saturation of secretory and reabsorption mechanisms by methotrexate. Our model accurately depicts the pharmacokinetics of nine courses of therapy in five patients. The model can also be used to simulate the kinetics of methotrexate for patients with impaired renal function.     

A modified two-portion absorption model to describe double-peak absorption profiles of ranitidine

BACKGROUND: The pharmacokinetics of oral drugs exhibiting double peaks cannot be adequately described by using conventional compartmental models. OBJECTIVE: To propose and evaluate a modified two-portion absorption model based on physiological and biopharmaceutical considerations to describe the double-peak concentration-time curve of ranitidine. MODEL DESIGN: The proposed model assumes that oral ranitidine is absorbed sequentially in two portions due to delayed gastric emptying, and thus includes a gut compartment in addition to the central and peripheral compartments. METHODS: Validation of the model was performed with respect to structural identifiability, parameter estimability and model applicability. Using initial estimates of parameters obtained from previous intravenous data, the model was used to fit oral ranitidine data from six subjects who manifested clear double-peak concentration-time profiles as well as from six subjects who showed irregular but apparent single-peak concentration-time curves. RESULTS: Based on goodness-of-fit criteria, the model fitted well for both double-peak and single-peak concentration-time curves of ranitidine (for the two groups: weighted residual sum of squares, 0.044 +/- 0.027 and 0.054 +/- 0.036; correlation between observed and model predicted concentrations, 0.995 +/- 0.003 and 0.995 +/- 0.005). Simulation studies with concentrations generated with 10% normally distributed random error showed that all model fitted parameters had good accuracy and reasonable precision. The mean percentage bias ranged from -7.0 to 28.6%, and the coefficient of variance was within 30% for the majority of parameters compared with the theoretical values. CONCLUSION: The modified two-portion absorption model may afford a useful approach to characterise the absorption phase and estimate pharmacokinetic parameters for drugs with two absorption peaks.     

The in vitro uptake and metabolism of lignocaine, procainamide and pethidine by tissues of the hindquarters of sheep

1. In vitro studies using tissue slices or tissue homogenates of liver, skeletal muscle, fat skin and blood were conducted to determine whether the uptake of procainamide, lignocaine and pethidine into the hindquarters of sheep was due to distribution or metabolism. Both homogenates and slice preparations of liver showed significant metabolism or uptake, confirming the viability of the preparations. 2. None of the drugs was metabolized in blood and there was minimal uptake of the drugs into the skin. 3. There was metabolism of pethidine in skeletal muscle and substantial uptake of pethidine into fat, indicating that the rapid rate of uptake and prolonged elution of pethidine in the hindquarters was due to both distribution and metabolism. 4. No metabolism of lignocaine in muscle was found, but there was substantial uptake into fat, indicating that the rapid rate of uptake and prolonged elution of lignocaine in the hindquarters was due to its distribution into fat. 5. There was negligible uptake of procainamide into either muscle or fat, presumably due to its relatively low lipophilicity.