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

A physiological flow model simulating the pregnant rat is constructed for methadone. The model includes brain, fetal, hepatic, intestinal, muscular, pulmonar, and renal tissues. Since methadone kinetics may provide valuable information for optimal therapy, an attempt is made to describe methadone kinetics in brain and other tissues simultaneously. The concentration-time profiles of methadone in various tissues after an i.v. bolus dose of 2 rng/kg are reasonably described by the model. The role of the different organs in the disposition of methadone is further explored by simulations. It is found that methadone is initially sequestered in lung tissues immediately after intravenous administration. Therefore, both venous and arterial blood pools are included in the model. Rapid uptake then takes place into vascular-rich organs, including kidneys, liver, and muscle, followed by redistribution into less penetrable organs, such as brain, fetal, and intestinal tissues. Data indicate that diffusional resistance governs the transfer of drug into brain, fetal, and intestinal tissues. Simulations suggest that muscular tissues play an important role in the rat and in man, becoming the major methadone reservoir. The tissue-to-blood partition coefficients derived from equilibrium conditions in this study are generally higher than those reported hitherto. The model is scaled up to a human to investigate whether it can be used to predict the concentration of methadone in different organs after a certain dose. Volume of distribution (Vd_ss) and biological half-life are consistent with earlier findings in man. The study is done by means of the GC-MS method with selected ion-monitoring where deuterated methadone is used as an internal standard.     

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.     

An extended physiological pharmacokinetic model of methadone disposition in the rat: Validation and sensitivity analysis

An extended physiological model of methadone disposition in the rat was constructed and evaluated in various tests of model validity. A separate circulation model of the fetus was included due to the large tissue concentration differences obtained after a constant rate infusion but also to propose the use of this type of model for optimization of toxicological tests. Simulations were performed with the animal model and scaled-up models of humans to elucidate the determinants of methadone dispostion. The rationale of the use of an extended model for methadone was also discussed.This work was supported by the Svenssons Foundation for Medical Research, the Royal Hvitfeld Establishment, and C. D. Carlssons Foundation.     

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

A physiological flow model simulating the pregnant rat is constructed for methadone. The model includes brain, fetal, hepatic, intestinal, muscular, pulmonar, and renal tissues. Since methadone kinetics may provide valuable information for optimal therapy, an attempt is made to describe methadone kinetics in brain and other tissues simultaneously. The concentration-time profiles of methadone in various tissues after an i.v. bolus dose of 2 mg/kg are reasonably described by the model. The role of the different organs in the disposition of methadone is further explored by simulations. It is found that methadone is initially sequestered in lung tissues immediately after intravenous administration. Therefore, both venous and arterial blood pools are included in the model. Rapid uptake then takes place into vascular-rich organs, including kidneys, liver, and muscle, followed by redistribution into less penetrable organs, such as brain, fetal, and intestinal tissues. Data indicate that diffusional resistance governs the transfer of drug into brain, fetal, and intestinal tissues. Simulations suggest that muscular tissues play an important role in the rat and in man, becoming the major methadone reservoir. The tissue-to-blood partition coefficients derived from equilibrium conditions in this study are generally higher than those reported hitherto. The model is scaled up to a human to investigate whether it can be used to predict the concentration of methadone in different organs after a certain dose. Volume of distribution (Vdss) and biological half-life are consistent with earlier findings in man. The study is done by means of the GC-MS method with selected ion-monitoring where deuterated methadone is used as an internal standard.     

A physiologically based pharmacokinetic model for theophylline disposition in the pregnant and nonpregnant rat

There are numerous studies which examine the disposition of theophylline from a traditional point of view. Information about the behaviour of drugs, including theophylline, is, however, very scarce when investigating the kinetics by means of a physiological flow model. This study is concerned with the development of a predictive analytical model for the pharmacokinetics of theophylline in nonpregnant and pregnant rats. This model postulates that specific organ or tissue masses may be simulated by compartments whose elements have physiological properties, e.g., tissue volumes, blood flow, and metabolic activity. A model has been developed that has blood, brain, hepatic, muscular, pulmonary, renal, and fetal tissues. With few exceptions, the agreement was good between predicted and calculated tissue data in the pregnant and nonpregnant rats. Finally, model simulations were performed to investigate the impact of different pulmonary extraction ratios on the concentration-time profile of theophylline in a hypothetical human patient.This study was supported by grants from the Swedish Council for Planning and Coordination of Research [(FRN)82/2090].     

Controlled release of tetracycline—III: A physiological pharmacokinetic model of the pregnant rat

A controlled tetracycline delivery device, consisting of a membrane enclosed trilaminate disc fabricated from a series of 2-hydroxyethylmethacrylate/methylmethacrylate copolymers, demonstrated the ability to deliver tetracycline at zero-order rates in vitro and in vivo in rats and was applied to study the pharmacokinetics of tetracycline in the pregnant rat. The trilaminate discs containing tetracycline were implanted in pregnant Sprague-Dawley rats on the eighth day of gestation. The animals were sacrificed on days 19, 20, and 21 of gestation in order to measure the distribution of the controlled release tetracycline in the maternal, fetal, and placental tissues. Constant plasma tetracycline levels were attained in both the maternal and fetal circulations after 4 to 5 days postimplantation of the trilaminate discs. Placental transfer of tetracycline appeared rapid and no partitioning of the drug was observed between the maternal and fetal plasma. Tetracycline levels did not differ significantly in the maternal and fetal soft tissues (liver, kidney, G. I. tract, muscle, placenta) as measured over the last 3 to 4 days of the animal's gestational period. Highest tetracycline concentrations were determined in the fetal bone samples. In addition, some accumulation of the drug occurred in the amniotic fluid. A flow-limited pharmacokinetic model was constructed to simulate the distribution of tetracycline, delivered at a constant rate from the trilaminate device, in the pregnant rats. Predictions of fetal growth and maternal and fetal tissue tetracycline concentrations were in good agreement with the experimental measurements. The ability of these copolymer systems to deliver tetracycline at zero-order rates over extended periods offers numerous potential therapeutic and investigational applications, especially where such drug delivery characteristics are beneficial to the elucidation of physiological rate mechanisms, as in the pregnant animal.     

Physiological pharmacokinetic model of ceftriaxone disposition in the rat and the effect of caffeine on the model

A Physiologically based pharmacokinetic model was used to describe the distribution and elimination of ceftriaxone in the rat. To validate the practical application of the model, the effect of caffeine on the model was also examined. The model consisted of eleven compartments representing the major sites for ceftriaxone distribution including carcass which served as a residual compartment. Elimination was represented by renal and hepatic (metabolic biliary) excretion with GI secretion and re-absorption. The drug concentrations in most of the tissues were simulated using flow limited equations while brain levels were simulated using membrane limited passive diffusion distribution. The experimental data were obtained by averaging the concentration of drug in the plasma and tissues of five rats after i.v. injection of ceftriaxone 100 mg/kg without and with caffeine 20 mg/kg. The data for the amount of ceftriaxone excreted in urine and gut contents were used to apportion total body clearance. HPLC with UV detection was used for the assay with 0.1–0.2 μ g/ml sensitivity. The great majority of drug concentrations with and without caffeine show reasonably good agreements to the simulation results within 20%. The effect of caffeine on renal and hepatic clearances was apparent with 18.8% and 18.6% increase in the model values, respectively.     

Constant-rate infusion of nicotine and cotinine. I. A physiological pharmacokinetic analysis of the cotinine disposition,and effects on clearance and distribution in the rat

The tissue partition of cotinine was measured by a GC-MS method following a 6-day constant-rate input of nicotine and cotinine to male rats by means of an osmotic minipump. The tissue-to-blood partition coefficients of cotinine were calculated for adipose (0.08), brain (0.48), heart muscle (0.55), intestinal (0.53), hepatic (0.64), pulmonary (0.50), renal (0.99), and skeletal muscle tissue (0.51), following the cotinine infusion. When nicotine was infused the tissue partitioning of cotinine increased by a factor of 2.3–4.9, depending on the tissue sampled. Another group of animals were killed at timed intervals from 10 min to 30 hr, after having received a single intravenous bolus dose of 0.5 mg cotinine, and the washout of cotinine was traced in blood and tissues. A physiological model was used to simulate the disposition of cotinine. Generally, the model-predicted concentrations were consistent with those found experimentally. The fractional uptake of cotinine into various tissues was simulated. Blood, intestinal, and skeletal muscle tissues embodied more than 70% of the total body load of the drug. Clearance (Cl),volume of distribution (V_d),and the biological half-life (t_1/2)were calculated both from the infusion study and by fitting a monoexponential model to the iv blood data of the rat. Significant differences were found in the apparent clearance calculated from the single iv bolus dose compared to the constant rate infusion. The volume of distribution was, however, consistent from both studies. The impact of a change in clearance was also simulated.The financial support from the Brown and Williamson Tobacco Company (USA) and the Åke Wiberg Foundation (Sweden) is gratefully acknowledged.     

Physiologically based pharmacokinetic prediction of p -phenylbenzoic acid disposition in the pregnant rat

Disposition of p -phenylbenzoic acid (PPBA) in the pregnant Wistar rat (for both mother and fetuses) was predicted by using a physiologically based pharmacokinetic model. This model was constructed from ten organs for the mother and eight organs for fetuses, with fetal blood flow based on anatomical circulation in uteri and skin–amniotic fluid drug exchange. Plasma total clearance, and renal and nonrenal clearances were measured, and transplacental clearance, skin–amniotic fluid clearances and fetal metabolic clearance were taken from previously reported compartment analysis. Tissue-to-plasma partition coefficients (K_p) for the mother were almost the same as that of the interstitial fluid space (0.055–0.28), except for the kidney and liver. In contrast, K_p values for fetuses were small when membrane restricted and diffusion-limited uptakes were assumed in brain, gut, spleen, muscle, fat, and skin for the mother. The physiological model successfully predicted the PPBA concentration–time profiles for both mother and fetuses after intravenous injection into the mother. Further, the model could be applied to predict the results obtained via two other routes of administration. Fetal plasma PPBA concentrations were well predicted after PPBA injection into umbilical vein and fetal muscle. © 1998 John Wiley & Sons, Ltd.     

Long-term measurement of cerebral blood flow and metabolism in a rat chronic hypoperfusion model

1. Rat bilateral common carotid artery occlusion (BCAO) was used as a chronic cerebral hypoperfusion model. We observed autoradiographically the long-term changes in regional cerebral blood flow (rCBF) and regional cerebral glucose utilization (rCGU) after 2 days and 1, 4 and 8 weeks of BCAO and in controls. Regions evaluated included the cerebral cortex, white matter and basal ganglia. Pathological changes were also observed with Klüver-Barrera and haematoxylin-eosin staining. 2. After 2 days, rCBF was significantly reduced to 33-58% in the cortex, white matter and amygdala and similar reductions were observed after 1 week. 3. After 4 weeks, rCBF recovered; however, rCBF remained significantly reduced in the occipital cortex, white matter, globus pallidus and substantia nigra. 4. After 2 days, rCGU was mostly maintained but, after 1 week, rCGU was reduced significantly to 40-70% in the cortex, white matter, basal ganglia and thalamus. Four weeks later, these reductions were no longer seen. 5. Rarefaction of the white matter was observed from 1 week. 6. These results showed that the BCAO in rats is an appropriate model for chronic cerebral hypoperfusion and that uncoupling of rCBF and rCGU was observed from 2 days until 4 weeks in the white matter.     

Tissue distribution of fentanyl and alfentanil in the rat cannot be described by a blood flow limited model

Traditionally, physiological pharmacokinetic models assume that arterial blood flow to tissue is the rate-limiting step in the transfer of drug into tissue parenchyma. When this assumption is made the tissue can be described as a well-stirred single compartment. This study presents the tissue washout concentration curves of the two opioid analgesics fentanyl and alfentanil after simultaneous 1-min iv infusions in the rat and explores the feasibility of characterizing their tissue pharmacokinetics, modeling each of the 12 tissues separately, by means of either a one-compartment model or a unit disposition function. The tissue and blood concentrations of the two opioids were measured by gas-liquid chromatography. The well-stirred one-compartment tissue model could reasonably predict the concentration-time course of fentanyl in the heart, pancreas, testes, muscle, and fat, and of alfentanil in the brain and heart only. In most other tissues, the initial uptake of the opioids was considerably lower than predicted by this model. The unit disposition functions of the opioids in each tissue could be estimated by nonparametric numerical deconvolution, using the arterial concentration times tissue blood flow as the input and measured tissue concentrations as the response function. The observed zero-time intercepts of the unit disposition functions were below the theoretical value of one, and were invariably lower for alfentanil than for fentanyl. These findings can be explained by the existence of diffusion barriers within the tissues and they also indicate that alfentanil is less efficiently extracted by the tissue parenchyma than the more lipophilic compound fentanyl. The individual unit disposition functions obtained for fentanyl and alfentanil in 12 rat tissues provide a starting point for the development of models of intratissue kinetics of these opioids. These submodels can then be assembled into full physiological models of drug disposition.Supported in part by the National Institute on Aging, RO1-AG-4594, the Anesthesia/ Pharmacology Research Foundation, and a travel grant from Janssen Pharma AB (Sweden).     

A physiological toxicokinetic model for inhaled propylene oxide in rat and human with special emphasis on the nose.

Chronic exposure to high concentrations of PO induced inflammation in the respiratory nasal mucosa (RNM) of rodents and, for concentrations >or= 300 ppm, caused nasal tumors. Considering the nose to be the most relevant target organ for PO-induced tumorigenicity, we developed a physiological toxicokinetic model for PO in rats and humans. It includes compartments for arterial, venous, and pulmonary blood, liver, muscle, fat, richly perfused tissues, lung, and nose. It simulates inhalation of PO, its distribution into tissues by blood flow, and its elimination by exhalation and metabolism. In nose, lung, and liver of rats, PO conjugation with glutathione (GSH), PO-induced GSH depletion, and formation of PO adducts to DNA are described. Also modeled are PO adducts to hemoglobin of rats and humans. Required partition coefficients and metabolic parameters were derived experimentally or from publications. In rats, simulated PO concentrations in blood and GSH levels in tissues agreed with measured data. If compared with reported values, levels of adducts with hemoglobin were underpredicted up to a factor of about 2. Adducts with DNA differed up to a factor of 3. Hemoglobin adducts predicted for PO-exposed workers were 1.5-1.9 times higher than the reported ones. Considering identical conditions of PO exposure, similar PO concentrations in RNM were modeled for rats and humans. Also, PO concentrations in blood, about 1/30th of those in RNM, were similar in both species. Since the model was evaluated on all available data in rats and humans, we consider it to be useful for estimating the risk from inhalation exposure to PO.     

基于GC-MS的心肌缺血大鼠血浆中内源性代谢物测定方法的建立

目的：建立GC-MS测定心肌缺血大鼠血浆中内源性代谢物的方法。方法：皮下注射异丙肾上腺素复制大鼠心肌缺血模型,采用DB-5MS Ultra Inert（30m×250μm,0.25μm）色谱柱,GC-MS进行程序升温,氦气（纯度>99.999%）为载气;无分流进样;流速为1mL·min-1;进样口温度设为250℃;进样量为2μL。质谱参数：离子源温度设为230℃;电子能量为70eV;电子倍增器电压1847V;电离方式EI。质谱采用全扫描方式（扫描范围30～550m/z）进行数据采集。自建对照品物质库,并参考气质工作站的数据库对内源性生物标志物进行鉴定指认,然后进行方法学考察,包括精密度、重现性、稳定性。结果：仪器与方法精密度、重复性和稳定性试验的相对峰面积RSD值均小于20%。结论：该方法快速、灵敏、准确、重复性好,可用于心肌缺血大鼠血浆中内源性代谢物的测定,该方法可应用于心肌缺血模型的代谢组学研究。     

Physiological pharmacokinetie model of adriamycin delivered via magnetic albumin microspheres in the rat

The influence of magnetic albumin microspheres on the disposition of adriamycin was evaluated. Adriamycin concentrations were monitored in multiple rat tissues for 48 hr after its intra-arterial administration (2 mg/kg) as a solution and associated with magnetic albumin microspheres. The magnetic dosage form was targeted to a predefined tail segment with a magnetic field strength of 8000 G applied for 30 min after dosing. A physiological pharmacokinetic model was used to describe the disposition of adriamycin following its administration from either dosage fcrm. The model developed for the data resulting from administration of adriamycin as a solution served as a foundation for the model developed for adriamycin resulting from the administration of adriamycin associated with the magnetic dosage form. The model for adriamycin following administration of the magnetic microspheres required additional relationships to describe the transport of adriamycin associated with the microspheres. For both models, the predicted adriamycin concentrations were in adequate agreement with the observed values. The present investigation demonstrates the use of a physiological pharmacokinetic modeling method to represent drug kinetics following its administration via a targeted drug delivery system.Research support from the Medical Research Council of New Zealand is gratefully acknowledged.     

A physiological model for the pharmacokinetics of methylene chloride in B6C3F1 mice following i.v. administrations

A physiologic mathematical model was developed to describe the time course of¹⁴C-methylene chloride (¹⁴CH₂Cl₂) distribution and elimination in mice following single i.v. administrations of 10 and 50mg/kg. A whole-body model was used to simulate¹⁴CH₂Cl₂ concentrations in blood and tissues, pulmonary clearance of unchanged¹⁴CH₂Cl₂, and metabolic conversion to¹⁴CO₂ and¹⁴CO as monitored by the appearances of these metabolites in expired breath. This diffusion-limited model was identified via a sequential optimization scheme using hybrid models for each compartment. Pulmonary elimination of unchanged¹⁴CH₂Cl₂ was modeled as a linear process while hepatic metabolism of¹⁴CH₂Cl₂ to the compounds¹⁴CO₂and¹⁴CO was described by a saturable metabolic rate term. The model adequately described the dose dependence in methylene chloride distribution and metabolism when simulations were compared to experimental data.     

The effect of three H2 receptor antagonists on the disposition of cyclosporin a in the in situ perfused rat liver model

The in situ, perfused rat liver model was used to investigate the effect of three H₂ receptor antagonists on the disposition of cyclosporin A (CyA) and the major human metabolite, AM1. Perfusion experiments, using standard techniques, were carried out on four groups (one control and three H₂-receptor antagonist-treated groups) of male Sprague-Dawley rats (300–350 g). All animals received CyA, 2.5 mg; the three treated groups received cimetidine (8 mg), ranitidine (3 mg), or famotidine (0.4 mg). Perfusated and bile samples were collected and assayed for CyA, AM1, and the H₂ receptor antagonists by HPLC. Results indicated that CyA perfusate concentrations in the controls and cimetidine and ranitidine-treated groups were not significantly different, although levels in the famotidine group were significantly higher at all times (p<0.05), except 30 min, compared to the controls. However, examination of the AM1 perfusate and bile data and the apparent metabolic clearance data indicated that CyA metabolism was still occurring, despite the presence of the H₂ receptor antagonist. It is suggested that the absence of a interaction may be attributed to a lack of specificity of the H₂ receptor antagonists for CYP3A, the isoenzyme responsible for CyA metabolism.     

Expansion of a PBPK model to predict disposition in pregnant women of drugs cleared via multiple CYP enzymes,including CYP2B6, CYP2C9 and CYP2C19

Aim

Conducting PK studies in pregnant women is challenging. Therefore, we asked if a physiologically-based pharmacokinetic (PBPK) model could be used to predict the disposition in pregnant women of drugs cleared by multiple CYP enzymes.

Methods

We expanded and verified our previously published pregnancy PBPK model by incorporating hepatic CYP2B6 induction (based on in vitro data), CYP2C9 induction (based on phenytoin PK) and CYP2C19 suppression (based on proguanil PK), into the model. This model accounted for gestational age-dependent changes in maternal physiology and hepatic CYP3A, CYP1A2 and CYP2D6 activity. For verification, the pregnancy-related changes in the disposition of methadone (cleared by CYP2B6, 3A and 2C19) and glyburide (cleared by CYP3A, 2C9 and 2C19) were predicted.

Results

Predicted mean post-partum to second trimester (PP : T₂) ratios of methadone AUC, C_max and C_min were 1.9, 1.7 and 2.0, vs. observed values 2.0, 2.0 and 2.6, respectively. Predicted mean post-partum to third trimester (PP : T₃) ratios of methadone AUC, C_max and C_min were 2.1, 2.0 and 2.4, vs. observed values 1.7, 1.7 and 1.8, respectively. Predicted PP : T₃ ratios of glyburide AUC, C_max and C_min were 2.6, 2.2 and 7.0 vs. observed values 2.1, 2.2 and 3.2, respectively.

Conclusions

Our PBPK model integrating prior physiological knowledge, in vitro and in vivo data, allowed successful prediction of methadone and glyburide disposition during pregnancy. We propose this expanded PBPK model can be used to evaluate different dosing scenarios, during pregnancy, of drugs cleared by single or multiple CYP enzymes.     

Physiological pharmacokinetics of solutes in the isolated perfused rat hindlimb: Characterization of the physiology with changing perfusate flow,protein content,and temperature using statistical moment analysis

Distribution of Evans Blue (EB), sucrose, and water into the isolated perfused rat hindlimb was studied under various conditions using the multiple indicator dilution (MID) technique. Statistical moment analyses of the outflow profiles for the EB, sucrose, and water were used to define the vascular, extravascular, and total water spaces, respectively. The varied perfusion conditions included albumin content (2, 4.7, and 7%), temperature (25, 37, and 42 C), perfusate flow rate (2, 4, 8, and 12 ml/min) and the presence/absence of red blood cells. The range of studies undertaken were chosen to represent the variety of conditions used in the preparation of both isolated animal and human limbs, the latter being particularly important in cytotoxic therapy for recurrent malignant melanoma. The distribution volumes of EB, sucrose, and water were dependent on the flow rate and the albumin content of perfusate. The normalized variances (CV ² ) of the markers were of the following order: sucrose (2.18) > water (1.58) > EB (0.68), indicating that some disequilibrium occurs during the capillary exchange of water and sucrose. It is suggested that a Krebs-Henseleit buffer containing 2% BSA is a suitable perfusate for most studies of the isolated rat hindlimb perfusion. The effect of albumin concentration manifests itself only at higher flows.We acknowledge the support of the National Heart Foundation (Queensland) and the Mayne Bequest Foundation. This study was conducted while the investigator (Z.Y. Wu) was in receipt of a WHO Research Training Grant. Professor M. S. Roberts also acknowledges the support of the Queensland and Northern New South Wales Lions Kidney & Medical Research Foundation.     

Prediction of the concentration of diphenylhydantoin in the brain using a physiological pharmacokinetic hybrid model

A physiological pharmacokinetic hybrid model was developed in order to predict the disposition kinetics of diphenylhydantoin (DPH) in the brain from the plasma concentration data of DPH. The model was constructed under the assumptions of well-stirred, plasma flow-limited and linear tissue disposition kinetics of DPH. DPH was administered intravenously to the rats at a dose of 10 mg/kg together with/without sodium salicylate (SA; 10 mg/kg) and the DPH concentrations in the plasma and brain were determined. Plasma protein binding of DPH was also determined using equilibrium dialysis technique. Then the model was tested for its predictability of DPH concentrations in the brian from the plasma data of DPH. It was found that the predicted values of DPH concentrations in the brian were in fair agreement with the experimental values in the rats of both treaments. The 2-fold increase in the brain concentrations of DPH by SA-coadministration was predicted well from the plasma concentration and plasma free fraction (f _p) data of DPH using the model. Therefore, the hybrid model was concluded to be very useful for the prediction of the concentrations of DPH in the brain from the plasma concentration data. Finally, DPH concentrations in the human brian was calculated using this model from plasma DPH data in the literature, yet the scale-up of this model to the human is not convinced.     

Residence time distributions of solutes in the perfused rat liver using a dispersion model of hepatic elimination: 1. Effect of changes in perfusate flow and albumin concentration on sucrose and taurocholate

The residence time distributions of sucrose and taurocholate have been determined from the outflow concentration-time profiles after bolus input into an in situperfused rat liver preparation. The normalized variance (and the dispersion number) appeared to be independent of perfusate flow rate (10 to 37ml/mm) and perfusate albumin concentration (0–5%). The apparent volume of distribution for sucrose appeared to increase with flow rate but was unaffected by the concentration of albumin (0–5%) present in the perfusate. The changes in taurocholate availability with flow rate were adequately accounted for by the dispersion model, whereas taurocholate availabilityprotein binding changes required an albumin-mediated transport model to be used in conjunction with the dispersion model.This study was supported by the National Health and Medical Research Council of Australia and the Dean's MRC (NZ) Fund.