Physiologically based pharmacokinetic model for pralmorelin hydrochloride in rats.

Pralmorelin hydrochloride (pralmorelin), consisting of six amino acid residues, is a growth hormone-releasing peptide. The aim of this study is to analyze the pharmacokinetics of pralmorelin after intravenous bolus administration to rats, and to develop a physiologically based pharmacokinetic (PB-PK) model to describe and predict the concentrations of pralmorelin in blood and tissues. Pralmorelin (3 mg/kg) was administered intravenously to 24 Sprague-Dawley rats. Groups of three rats were sacrificed by decapitation at each designated time point (up to 4 h), and plasma and tissues (brain, lung, heart, liver, kidney, small intestine, muscle, adipose, and skin) were collected. Bile was also pooled until decapitation. The concentration of pralmorelin in samples was determined by liquid chromatography-tandem mass spectrometry. Plasma concentrations of pralmorelin declined rapidly in a biexponential manner. Biliary excretion of pralmorelin was so rapid that 80% of the dose was recovered unchanged in the bile within 1 h after administration. The distribution parameters in each tissue were obtained by using a hybrid model and an integration plot. They revealed that the distribution of pralmorelin into liver was blood flow-limited, and its distribution was permeability-limited in all other tissues. The PB-PK model developed in this study well described the time courses of pralmorelin concentration in the blood and tissues of rats.     

Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution

We present a sub-compartmentalized model of drug distribution in tissue that extends existing approaches based on the well-stirred tissue model. It is specified in terms of differential equations that explicitly account for the drug concentration in erythrocytes, plasma, interstitial and cellular space. Assuming, in addition, steady state drug distribution and by lumping the different sub-compartments, established models to predict tissue-plasma partition coefficients can be derived in an intriguingly simple way. This direct link is exploited to explicitly construct and parameterize the sub-compartmentalized model for moderate to strong bases, acids, neutrals and zwitterions. The derivation highlights the contributions of the different tissue constituents and provides a simple and transparent framework for the construction of novel tissue distribution models.     

Physiologically based pharmacokinetic model for vinylidene chloride

Vinylidene chloride (VDC), a potent hepatotoxin and suspected carcinogen, is metabolized by mixed-function oxidases into a reactive metabolite(s) which is responsible for its toxicity. The metabolite is detoxified by glutathione (GSH), and liver GSH status is an important factor in the expression of VDC toxicity. A physiologically based pharmacokinetic (PB-PK) model has been developed for VDC in the rat based on oxidative metabolism of VDC and subsequent GSH detoxification of metabolite. The model offers insight into the complex interrelationship between the processes of absorption, metabolism, and GSH conjugation, and simulates the manner in which these factors operate in regulating VDC toxicity. The PB-PK model successfully predicts blood, tissue, and exhaled air concentrations of VDC, and liver GSH levels as a function of dose and route of administration. The model also explains the complex dose-response mortality curves seen with VDC. Because of the low blood:air partition coefficient of VDC and its saturable metabolism, the amount of VDC dose that is metabolized is sensitive to the rate of absorption. After an intravenous bolus dose, most of the administered VDC is exhaled unchanged within a few minutes. Blood VDC half-life is not representative of metabolism rates but to reequilibration of VDC from fat. Rats with greater fat content, therefore, display longer VDC blood half-lives. Simulations are shown to demonstrate the strength of PB-PK modeling techniques in understanding the kinetic behavior of VDC in the rat under a variety of experimental conditions.     

Physiologically based pharmacokinetic model for topotecan in mice

Topotecan is a chemotherapeutic agent of choice for the second-line treatment of recurrent ovarian cancer. In this article, we have developed a physiologically based pharmacokinetic model to characterize and predict topotecan concentrations in mouse plasma and tissues. Single intravenous (IV) doses (5, 10 and 30 mg/kg) of topotecan were administered to male Swiss Webster mice, with plasma and tissue samples collected over 24 h, and with sample analysis by high performance liquid chromatography. Topotecan disposition in the lungs, heart, muscle, skin, spleen, gut, liver, brain and adipose was described by perfusion rate-limited compartments, whereas the testes and intraperitoneal (IP) fluid were described with permeability rate-limited compartments. The kidneys were modeled as a permeability rate-limited compartment with nonlinear efflux. The model included enterohepatic recycling of topotecan, with re-absorption of drug secreted in the bile and nonlinear bioavailability. Topotecan demonstrated dose-dependent, nonlinear pharmacokinetics and its elimination was described by nonlinear clearance from the liver and a parallel nonlinear and linear clearance from the kidneys. Mean tissue-to-plasma partition coefficients ranged from 0.123 (brain) to 55.3 (kidney). The model adequately characterized topotecan pharmacokinetics in plasma and tissue for all three doses. Additionally, the model provided good prediction of topotecan pharmacokinetics from several external data sets, including prediction of topotecan tissue pharmacokinetics following administration of 1 or 20 mg/kg IV, and prediction of plasma pharmacokinetics following doses of 1, 1.25, 15, 20 and 80 mg/kg IV and 20 mg/kg IP.     

Physiologically based pharmacokinetic model for methanol in rats, monkeys, and humans.

The pharmacokinetics of methanol and formate were characterized in male Fischer-344 rats and rhesus monkeys exposed to methanol vapor concentrations between 50 and 2000 ppm for 6 hr. End-of-exposure blood methanol concentrations were not directly proportional to the atmospheric concentration. The methanol exposures did not cause an elevation in blood formate concentrations. After an intravenous dose of [14C]methanol in rats, metabolism, exhalation, and renal excretion contributed 96.6, 2.6, and 0.8%, respectively, to the elimination of blood methanol concentrations. These values and the calculated renal methanol extraction efficiency (0.007) are nearly identical to those for humans after low doses of methanol. A physiologically based pharmacokinetic model was developed to simulate the in vivo data. In order to simulate the observed blood methanol concentrations in the inhalation studies in rats, a double pathway for methanol metabolism to formaldehyde was used. One path used rodent catalase Km and Vmax values and the other used a smaller Km and Vmax to simulate an enzyme with a higher affinity and lower capacity. The lack of proportionality observed in end-of-exposure blood methanol concentrations may be due to saturation of an enzyme with higher affinity and lower capacity than catalase. The physiologically based pharmacokinetic model was modified to simulate the monkey data and was scaled-up for humans. In order to simulate the monkey blood methanol concentrations, the use of rodent catalase parameters for methanol metabolism was required. This finding suggests that primates and rodents may be similar in the initial step of methanol metabolism after low methanol doses. Previously published human urinary methanol excretion data was successfully simulated by the model. The models were used to predict the atmospheric methanol concentration range over which the laboratory species exhibit quantitative similarities with humans. Below 1200 ppm, all three species exhibit similar end-of-exposure blood methanol concentrations and a linear relationship between atmospheric and blood methanol concentrations. At higher atmospheric concentrations, external and internal methanol concentrations increase desparately, suggesting that delivered dose rather than exposure concentration should be used in interpreting data from high-dose studies.     

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.     

Physiologically based pharmacokinetic modeling of cyclotrimethylenetrinitramine in male rats

A physiologically based pharmacokinetic (PBPK) model for simulating the kinetics of cyclotrimethylene trinitramine (RDX) in male rats was developed. The model consisted of five compartments interconnected by systemic circulation. The tissue uptake of RDX was described as a perfusion‐limited process whereas hepatic clearance and gastrointestinal absorption were described as first‐order processes. The physiological parameters for the rat were obtained from the literature whereas the tissue : blood partition coefficients were estimated on the basis of the tissue and blood composition as well as the lipophilicity characteristics of RDX (logP = 0.87). The tissue : blood partition coefficients (brain, 1.4; muscle, 1; fat, 7.55; liver, 1.2) obtained with this algorithmic approach were used without any adjustment, since a focused in vitro study indicated that the relative concentration of RDX in whole blood and plasma is about 1 : 1. An initial estimate of metabolic clearance of RDX (2.2 h^?1 kg^?1) was obtained by fitting PBPK model simulations to the data on plasma kinetics in rats administered 5.5 mg kg^?1 i.v. The rat PBPK model without any further change in parameter values adequately simulated the blood kinetic data for RDX at much lower doses (0.77 and 1.04 mg ^?1 i.v.), collected in this study. The same model, with the incorporation of a first order oral absorption rate constant (K_a 0.75 h^?1), reproduced the blood kinetics of RDX in rats receiving a single gavage dose of 1.53 or 2.02 mg kg^?1. Additionally, the model simulated the plasma and blood kinetics of orally administered RDX at a higher dose (100 mg kg^?1) or lower doses (0.2 or 1.24 mg kg^?1) in male rats. Overall, the rat PBPK model for RDX with its parameters adequately simulates the blood and plasma kinetic data, obtained following i.v. doses ranging from 0.77 to 5.5 mg kg^?1 as well as oral doses ranging from 0.2 to 100 mg kg^?1. Published in 2009 by John Wiley & Sons, Ltd.     

Physiologically based pharmacokinetic model development and simulations for ethylene dichloride (1,2-dichloroethane) in rats

1,2-Dichloroethane (ethylene dichloride, EDC, CAS No. 107-06-2) is a chemical intermediate used in the production of vinyl chloride, trichloroethylene, vinylidene chloride, and trichloroethane. EDC is listed as a Hazardous Air Pollutant (HAP). As such, a need has been identified for a quantitative understanding of the hazards of EDC exposure by the inhalation route. Use of physiologically based pharmacokinetic (PBPK) modeling for route-to-route extrapolation of existing and a future toxicity studies conducted by the oral route may facilitate the quantitative evaluation of potential hazards posed by inhalation of EDC. PBPK models for the disposition of EDC by rats have been previously described, but a need to update the model structure and parameter values was identified based on the current understanding of kinetics of conjugation reactions mediated by glutathione-S-transferases (GSTs) and lack of fit to kinetic data that were not part of the development of previous models. Model structure updates included the addition of extrahepatic metabolism by unspecified enzymes (most likely GSTs or cytochrome P450 enzymes). Chemical-specific disposition parameters were recalibrated and provided good simulations for the majority of the large pharmacokinetic database for single or repeated exposure to EDC via inhalation, gavage, or iv injection in four strains of rats.     

Physiologically based pharmacokinetic model development and simulations for ethylene dichloride (1,2-dichloroethane) in rats

1,2-Dichloroethane (ethylene dichloride, EDC, CAS No. 107-06-2) is a chemical intermediate used in the production of vinyl chloride, trichloroethylene, vinylidene chloride, and trichloroethane. EDC is listed as a Hazardous Air Pollutant (HAP). As such, a need has been identified for a quantitative understanding of the hazards of EDC exposure by the inhalation route. Use of physiologically based pharmacokinetic (PBPK) modeling for route-to-route extrapolation of existing and a future toxicity studies conducted by the oral route may facilitate the quantitative evaluation of potential hazards posed by inhalation of EDC. PBPK models for the disposition of EDC by rats have been previously described, but a need to update the model structure and parameter values was identified based on the current understanding of kinetics of conjugation reactions mediated by glutathione-S-transferases (GSTs) and lack of fit to kinetic data that were not part of the development of previous models. Model structure updates included the addition of extrahepatic metabolism by unspecified enzymes (most likely GSTs or cytochrome P450 enzymes). Chemical-specific disposition parameters were recalibrated and provided good simulations for the majority of the large pharmacokinetic database for single or repeated exposure to EDC via inhalation, gavage, or iv injection in four strains of rats.     

Physiologically based pharmacokinetic model for T84.66: A monoclonal anti-CEA antibody

Antibodies directed against tumor associated antigens are being increasingly used for detection and treatment of cancers; however, there is an incomplete understanding of the physiological determinants of antibody pharmacokinetics and tumor distribution. The purpose of this study is to (a) compare the plasma pharmacokinetics of T84.66, a monoclonal anti-CEA antibody directed against tumor associated carcinoembryonic antigen (CEA), in control and CEA expressing LS174T xenograft bearing mice, and (b) to develop a physiologically based pharmacokinetic (PBPK) model capable of integrating the influence of CEA and the IgG salvage receptor, FcRn, on T84.66 disposition. T84.66 pharmacokinetics were studied following i.v. administration (1, 10, 25 mg/kg) in control and xenograft bearing mice. In control mice, no significant differences in clearance were observed across the dose range studied. In mice bearing xenograft tumors, clearance was increased by four- to sevenfold, suggesting the presence of a “target mediated” elimination pathway. T84.66 plasma disposition was characterized with a PBPK model, and the model was applied to successfully predict antibody concentrations in tumor tissue. The PBPK model will be used to assist in the development of antibody-based targeting strategies for CEA-positive tumors. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1582–1600, 2010     

Effects of alcohol-metabolizing enzyme inhibitors and beta-lactam antibiotics on ethanol elimination in rats

The in vivo effects of alcohol-metabolizing enzyme inhibitors and beta-lactam antibiotics upon the ethanol elimination rate were examined in rats. Intravenous administration of ethanol caused a dose-dependent increase in blood ethanol level, and the ethanol elimination could be well described by a two compartment model. Pretreatment of rats with enzyme inhibitors caused a marked decrease in the ethanol elimination rate associated with the depression of the enzyme activities. Fasting of the animals caused a decrease in the ethanol elimination rate per animal associated with a decrease in the liver weight. However, no alteration was evident when the rate was expressed as the rate per g of liver. When animals were pretreated with a high dose of N-methyltetrazolethiol (NMTT)- containing beta-lactam antibiotics or NMTT itself, which causes a disulfiram-like reaction, the ethanol elimination rate per animal was depressed concomitant with an increase in the blood acetaldehyde level. The ethanol elimination rate in these animals showed lower values even when expressed as the rate per g liver. On the other hand, administration of cephems without NMTT, which cause no disulfiram-like reaction, led to a slight decline in the elimination rate per animal, although no alteration was detected when the rate was expressed as the rate per g liver. The findings indicated that the ethanol elimination in vivo per animal is regulated by the total capacity of the alcohol-metabolizing enzyme activities in the whole liver.     

Physiological pharmacokinetic model for the distribution and elimination of tenoxicam

A physiologically based pharmacokinetic model for tenoxicam distribution and excretion in the rat was developed. The drug concentrations in plasma and all the tissues except testis were simulated using flow-limited equations, while testis concentrations were calculated using a membrane-limited passive diffusion equation. The elimination of tenoxicam was described in the model by renal and hepatic (metabolic and biliary) excretion with gastro-intestinal secretion and reabsorption. In order to validate the model, 15 tissue samples, plasma (for free and total concentration), urine and feces samples were collected and assayed by HPLC after i.v. injection of tenoxicam (4.5 mg/kg). Good agreements between simulation and experimental data over a 24-h period following drug administration were obtained for plasma and tissues. The terminal half-life of tenoxicam was 8.8 h in plasma and ranged in tissues from 6.1 h in intestine to 10.6 h in brain. The fraction of free tenoxicam in plasma ranged from 1.2 to 2.1% of the total tenoxicam concentration (5.7–21.9 μ/ml).     

基于ACSL Math建立依地普仑生理药代动力学模型

目的利用ACSLMath初步建立依地普仑在人体的血流限速生理模型,并进行不同给药剂量间的外推．评估药物的体内特征。方法运用ACSL专业软件对模型进行模拟,并将预测值和文献值比较。结果预测值和文献值的相关性良好,药代动力学参数基本一致。结论模型可以较好地预测依地普仑在人体的血药时间过程．但模型仍需进一步优化和修订。     

Physiologically based pharmacokinetic/pharmacodynamic model for acrylamide and its metabolites in mice, rats, and humans

A physiologically based pharmacokinetic model was developed for acrylamide (AA) and three of its metabolites: glycidamide (GA) and the glutathione conjugates of acrylamide (AA-GS) and glycidamide (GA-GS). Liver GA-DNA adducts and hemoglobin (Hb) adducts with AA and GA were included as pharmacodynamic components of the model. Serum AA and GA concentrations combined with urinary elimination levels for all four components from male and female mice and rats were simulated from iv and oral administration of 0.1 mg/kg AA or 0.12 mg/kg GA. Adduct formation and decay rates were determined from a 6 week exposure to approximately 1 mg/kg AA in the drinking water and subsequent 6 week nonexposure period. Human urinary excretion data and Hb adduct data were utilized to extrapolate to a human model. The steady-state human liver GA-DNA adduct level from exposure to background levels of AA in the diet was predicted to be between 0.06 and 0.26 adducts per 10(8) nucleotides.     

Physiologically based pharmacokinetic modeling of dibromoacetic acid in F344 rats

A novel physiologically based pharmacokinetic (PBPK) model structure, which includes submodels for the common metabolites (glyoxylate (GXA) and oxalate (OXA)) that may be involved in the toxicity or carcinogenicity of dibromoacetic acid (DBA), has been developed. Particular attention is paid to the representation of hepatic metabolism, which is the primary elimination mechanism. DBA-induced suicide inhibition is modeled by irreversible covalent binding of the intermediate metabolite α-halocarboxymethylglutathione (αH1) to the glutathione-S-transferase zeta (GSTzeta) enzyme. We also present data illustrating the presence of a secondary non-GSTzeta metabolic pathway for DBA, but not dichloroacetic acid (DCA), that produces GXA. The model is calibrated with plasma and urine concentration data from DBA exposures in female F344 rats through intravenous (IV), oral gavage, and drinking water routes. Sensitivity analysis is performed to confirm identifiability of estimated parameters. Finally, model validation is performed with data sets not used during calibration. Given the structural similarity of dihaloacetates (DHAs), we hypothesize that the PBPK model presented here has the capacity to describe the kinetics of any member or mixture of members of this class in any species with the alteration of chemical-and species-specific parameters.     

Tissue distribution of beta-lactam antibiotics, cefotiam and cefmenoxime in the lungs of sheep

The present study was performed to investigate the distribution of beta-lactam antibiotics, cefotiam (CTM) and cefmenoxime (CMX) in pulmonary tissue of sheep. The animals were prepared to form chronic lung-lymph fistula for the collection of lung lymph. CTM and CMX were administered bolus-intravenously at doses of 20 mg/kg and 40 mg/kg, respectively, and serum and lymph levels of each drug were measured by bioassay method. Antibiotic levels of serum or lymph increased to a peak within 15 minutes after injection and then decreased rapidly. Measurable concentrations persisted for 240 minutes after the injection. Ratios of lung lymph to serum concentrations of CTM and CMX within 1 hour after the injection ranged 0.7 to 1.3, and 0.9 to 1.3, respectively. In addition, CMX levels in serum, lung lymph and tissues of both right and left lung were compared in anesthetized sheep to which CMX 50 mg/kg was given. Ratios of lung lymph and tissue concentrations of CMX in right and left lung to serum concentration were 0.76, 0.14 and 0.13, respectively. These results indicate that CTM and CMX were well distributed in interstitial fluid (lung lymph), and the levels of CMX in tissues of both right and left lung were markedly lower than those of lung lymph.     

Physiologically based pharmacokinetic model for developmental exposures to TCDD in the rat.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent developmental toxicant in rodents, and these effects occur at exposures similar to background human body burdens. A physiologically based pharmacokinetic (PBPK) model can aid in quantitatively describing the relationship between exposure, dose, and response. The aim of this work was the development a PBPK model to describe the relationship between maternal TCDD exposure and fetal TCDD concentrations during critical windows of susceptibility in the rat. This PBPK model is a modification of an eight-compartment model that describes the adult female rat. The modified model reduces the compartments from eight to four maternal compartments (liver, fat, placenta and rest of the body). Activation of the placental compartment and a separate fetal compartment occurs during gestation. The systemic circulation connects the maternal compartments. The physiological and biochemical parameters were obtained from the literature. The model validation used experimental data from acute and subchronic exposures prior to and during gestation. The simulations predict the TCDD tissue concentrations of the maternal compartments within the standard deviation of the experimental data. The model overestimates the fetal concentrations by approximately a factor of two at low subchronic exposures, but does predict the fetal tissue concentrations within the range of the experimental data at the higher exposures. This model may provide a framework for the development of a human PBPK model to estimate fetal TCDD concentrations in human health risk assessments.     

Physiologically based pharmacokinetic and pharmacodynamic model for the inhibition of acetylcholinesterase by diisopropylfluorophosphate

Organophosphate (OP) exposure can be lethal at high doses while lower doses may impair performance of critical tasks. The ability to predict such effects for realistic exposure scenarios would expedite OP risk assessment. To this end, a physiologically based model for diisopropylfluorophosphate (DFP) pharmacokinetics and acetylcholinesterase (AChE) inhibition was developed in mammals. DFP tissue:blood partition coefficients, rates of DFP hydrolysis by esterases, and DFP-esterase bimolecular inhibition rate constants were determined in rat tissue homogenates. Other model parameters were scaled for rats and mice using standard allometric relationships. These DFP-specific parameter values were used with the model to simulate expected in vivo pharmacokinetic data from mice and rats. Literature data were used for model validation. DFP concentrations in mouse plasma and brain were successfully simulated after a single iv injection (B.R. Martin, 1985, Toxicol. Appl. Pharmacol. 77, 275-284). AChE inhibition and AChE resynthesis data from this study were also simulated. Effects of repeated, subcutaneous DFP dosing on AChE activity in rat plasma and brain (H. Michalek, A. Meneguz, and G.M. Bisso, 1982, Arch. Toxicol., Suppl. 5, 116-119; M.E. Traina and L.A. Serpietri, 1984, Biochem. Pharmacol. 33, 645-653) were also simulated well, but the return of brain AChE activity to basal levels after cessation of repeated dosing was not as well described. The initial model structure returned brain AChE activity to the original level, while in the laboratory studies brain AChE never returned to basal levels, even at 35 days after the last dose. These data suggest modulation of AChE synthesis with prolonged DFP exposure. This study demonstrated the possibility of using a model based on mammalian physiology and biochemistry to simulate in vivo data on DFP pharmacokinetics and AChE inhibition. Scaling of the model between rats and mice was also successful. The approach holds promise for predictive simulation of organophosphate-mediated AChE inhibition in humans.