Quantitative prediction of in vivo drug clearance and drug interactions from in vitro data on metabolism, together with binding and transport.

It is of great importance to predict in vivo pharmacokinetics in humans based on in vitro data. We summarize recent findings of the quantitative prediction of the hepatic metabolic clearance from in vitro studies using human liver microsomes, hepatocytes, or P450 isozyme recombinant systems. Furthermore, we propose a method to predict pharmacokinetic alterations caused by drug-drug interactions that is based on in vitro metabolic inhibition studies using human liver microsomes or human enzyme expression systems. Although we attempt to avoid the false negative prediction, the inhibitory effect was underestimated in some cases, indicating the possible contribution of the active transport into hepatocytes and/or interactions at the processes other than the hepatic metabolism, such as the metabolism and transport processes during gastrointestinal absorption.

[1]  H Suzuki,et al.  [Kinetic analysis of hepatobiliary transport of drugs: importance of carrier-mediated transport]. , 1995, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan.

[2]  R. Kato,et al.  The importance of substrate concentration in determining cytochromes P450 therapeutically relevant in vivo. , 1994, Pharmacogenetics.

[3]  W. Trager,et al.  Use of midazolam as a human cytochrome P450 3A probe: I. In vitro-in vivo correlations in liver transplant patients. , 1994, The Journal of pharmacology and experimental therapeutics.

[4]  Grant R. Wilkinson,et al.  A physiological approach to hepatic drug clearance , 1975 .

[5]  D. Warnock,et al.  Pharmacokinetics of ketoconazole in normal subjects. , 1981, The Journal of antimicrobial chemotherapy.

[6]  T Iwatsubo,et al.  PREDICTION OF IN VIVO DRUG DISPOSITION FROM IN VITRO DATA BASED ON PHYSIOLOGICAL PHARMACOKINETICS , 1996, Biopharmaceutics & drug disposition.

[7]  T. Andersson,et al.  Omeprazole: pharmacokinetics and metabolism in man. , 1989, Scandinavian journal of gastroenterology. Supplement.

[8]  J S Harmatz,et al.  Inhibition of desipramine hydroxylation in vitro by serotonin-reuptake-inhibitor antidepressants, and by quinidine and ketoconazole: a model system to predict drug interactions in vivo. , 1994, The Journal of pharmacology and experimental therapeutics.

[9]  Y. Sugiyama,et al.  Prediction of in vivo nonlinear first-pass hepatic metabolism of YM796 from in vitro metabolic data. , 1998, The Journal of pharmacology and experimental therapeutics.

[10]  Kaoru Kobayashi,et al.  Identification of cytochrome P450 isoforms involved in citalopram N-demethylation by human liver microsomes. , 1997, The Journal of pharmacology and experimental therapeutics.

[11]  R. Gugler,et al.  Omeprazole inhibits oxidative drug metabolism , 1985 .

[12]  J B Houston,et al.  Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. , 1994, Biochemical pharmacology.

[13]  M. Kendall,et al.  The effect of age on the pharmacokinetics of metoprolol and its metabolites. , 1981, British journal of clinical pharmacology.

[14]  M. Grant,et al.  Human adult hepatocytes in primary monolayer culture. Maintenance of mixed function oxidase and conjugation pathways of drug metabolism. , 1987, Biochemical pharmacology.

[15]  H. Yamazaki,et al.  Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. , 1994, The Journal of pharmacology and experimental therapeutics.

[16]  J. Houston,et al.  In vivo disposition of caffeine predicted from hepatic microsomal and hepatocyte data. , 1995, Drug metabolism and disposition: the biological fate of chemicals.

[17]  J. Kolars,et al.  First-pass metabolism of cyclosporin by the gut , 1991, The Lancet.

[18]  M. Rowland,et al.  Correlation between in‐vitro microsomal enzyme activity and whole organ hepatic elimination kinetics: analysis with a dispersion model , 1986, The Journal of pharmacy and pharmacology.

[19]  M. Yamazaki,et al.  Carrier-mediated active transport of histamine H2 receptor antagonists, cimetidine and nizatidine, into isolated rat hepatocytes: contribution of type I system. , 1994, The Journal of pharmacology and experimental therapeutics.

[20]  P. Beaune,et al.  Cytochrome P 450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues. , 1990, The Journal of pharmacology and experimental therapeutics.

[21]  R. Kato,et al.  Cytochrome P450 mediated metabolism of diazepam in human and rat: involvement of human CYP2C in N-demethylation in the substrate concentration-dependent manner. , 1993, Pharmacogenetics.

[22]  D. Shen,et al.  Oral first‐pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A‐mediated metabolism , 1996, Clinical pharmacology and therapeutics.

[23]  J. Houston,et al.  Prediction of in vivo disposition from in vitro systems: clearance of phenytoin and tolbutamide using rat hepatic microsomal and hepatocyte data. , 1995, The Journal of pharmacology and experimental therapeutics.

[24]  Tucker Gt,et al.  The rational selection of drug interaction studies: implications of recent advances in drug metabolism. , 1992 .

[25]  M. Rowland,et al.  Models of hepatic drug clearance: discrimination between the ‘well stirred’ and ‘parallel‐tube’ models , 1983, The Journal of pharmacy and pharmacology.

[26]  M. Chiba,et al.  Metabolism: Scaling-up from In Vitro to Organ and Whole Body , 1994 .

[27]  D. Back,et al.  In vitro inhibition studies of tolbutamide hydroxylase activity of human liver microsomes by azoles, sulphonamides and quinolines. , 1988, British journal of clinical pharmacology.

[28]  Y. Sugiyama,et al.  Prediction of in vivo hepatic metabolic clearance of YM796 from in vitro data by use of human liver microsomes and recombinant P-450 isozymes. , 1997, The Journal of pharmacology and experimental therapeutics.

[29]  J. Miners,et al.  Validation of the tolbutamide metabolic ratio for population screening with use of sulfaphenazole to produce model phenotypic poor metabolizers , 1990, Clinical pharmacology and therapeutics.

[30]  R. Thomas,et al.  The metabolic fate of tolbutamide in man and in the rat. , 1966, Journal of medicinal chemistry.

[31]  E. Johnson,et al.  Influence of food on the pharmacokinetics of ketoconazole , 1984, Antimicrobial Agents and Chemotherapy.

[32]  R. Gugler,et al.  Omeprazole inhibits oxidative drug metabolism. Studies with diazepam and phenytoin in vivo and 7-ethoxycoumarin in vitro. , 1985, Gastroenterology.

[33]  L. Benet,et al.  Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P‐glycoprotein: Implications for drug delivery and activity in cancer chemotherapy , 1995, Molecular carcinogenesis.

[34]  B. Hoener,et al.  Predicting the hepatic clearance of xenobiotics in humans from in vitro data , 1994, Biopharmaceutics & drug disposition.

[35]  C. L. Ferguson,et al.  Torsades de pointes occurring in association with terfenadine use. , 1990, JAMA.

[36]  D. Greenblatt,et al.  Inhibitors of alprazolam metabolism in vitro: effect of serotonin-reuptake-inhibitor antidepressants, ketoconazole and quinidine. , 1994, British journal of clinical pharmacology.

[37]  M Rowland,et al.  Differentiation of absorption and first‐pass gut and hepatic metabolism in humans: Studies with cyclosporine , 1995, Clinical pharmacology and therapeutics.

[38]  Y. Sugiyama,et al.  Prediction of species differences (rats, dogs, humans) in the in vivo metabolic clearance of YM796 by the liver from in vitro data. , 1997, The Journal of pharmacology and experimental therapeutics.

[39]  D. Jones,et al.  Models of hepatic elimination , 1986, Hepatology.

[40]  J. Miners,et al.  Tolbutamide hydroxylation by human liver microsomes. Kinetic characterisation and relationship to other cytochrome P-450 dependent xenobiotic oxidations. , 1988, Biochemical pharmacology.

[41]  C. Libersa,et al.  Mexiletine metabolism in vitro by human liver. , 1990, Drug metabolism and disposition: the biological fate of chemicals.

[42]  C. Crespi Xenobiotic-metabolizing human cells as tools for pharmacological and toxicological research , 1995 .

[43]  G R Wilkinson,et al.  Prediction of hepatic extraction ratio from in vitro measurement of intrinsic clearance. , 1977, The Journal of pharmacology and experimental therapeutics.

[44]  J. Houston,et al.  Glucuronidation in vitro and in vivo. Comparison of intestinal and hepatic conjugation of morphine, naloxone, and buprenorphine. , 1987, Drug metabolism and disposition: the biological fate of chemicals.

[45]  J. Kolars,et al.  Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. , 1992, The Journal of clinical investigation.

[46]  T. Izumi,et al.  Prediction of the human pharmacokinetics of troglitazone, a new and extensively metabolized antidiabetic agent, after oral administration, with an animal scale-up approach. , 1996, The Journal of pharmacology and experimental therapeutics.

[47]  D. Greenblatt,et al.  Metabolism of Drugs by Cytochrome P450 3A Isoforms , 1995, Clinical pharmacokinetics.

[48]  Y. Sugiyama,et al.  Na(+)-independent multispecific anion transporter mediates active transport of pravastatin into rat liver. , 1993, The American journal of physiology.

[49]  E. Nelson,et al.  Kinetics of carboxytolbutamide excretion following tolbutamide and carboxytolbutamide administration. , 1961, The Journal of pharmacology and experimental therapeutics.

[50]  Y. Sai,et al.  Active Secretion of Drugs from the Small Intestinal Epithelium in Rats by P‐Glycoprotein Functioning as an Absorption Barrier , 1996, The Journal of pharmacy and pharmacology.

[51]  R. Hook,et al.  Pharmacokinetics and biotransformation studies of terfenadine in man. , 1982, Arzneimittel-Forschung.

[52]  P. Beaune,et al.  Expression of human liver cytochrome P450 IIIA4 in yeast. A functional model for the hepatic enzyme. , 1990, European journal of biochemistry.

[53]  D. Wortham,et al.  Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences. , 1993, JAMA.

[54]  Y. Sugiyama,et al.  Applications and prospects for physiologically based pharmacokinetic (PB-PK) models involving pharmaceutical agents. , 1995, Toxicology letters.

[55]  E. Mini,et al.  Pharmacokinetic Drug Interactions of Macrolides , 1992, Clinical pharmacokinetics.

[56]  D. Greenblatt,et al.  Inhibition of terfenadine metabolism in vitro by azole antifungal agents and by selective serotonin reuptake inhibitor antidepressants: relation to pharmacokinetic interactions in vivo. , 1996, Journal of clinical psychopharmacology.

[57]  T. Kamataki,et al.  Oxidative metabolism of omeprazole in human liver microsomes: cosegregation with S-mephenytoin 4'-hydroxylation. , 1993, The Journal of pharmacology and experimental therapeutics.

[58]  D. Greenblatt,et al.  In Vitro Prediction of the Terfenadine‐Ketoconazole Pharmacokinetic Interaction , 1994, Journal of clinical pharmacology.

[59]  M. Kristensen,et al.  SULPHAPHENAZOLE-INDUCED HYPOGLYCAEMIC ATTACKS IN TOLBUTAMIDE-TREATED DIABETICS. , 1963, Lancet.

[60]  T. Izumi,et al.  Pharmacokinetics of troglitazone, an antidiabetic agent: prediction of in vivo stereoselective sulfation and glucuronidation from in vitro data. , 1997, The Journal of pharmacology and experimental therapeutics.

[61]  M. Lieh-Lai,et al.  Drug-Induced Torsades De Pointes: A Possible Interaction of Terfenadine and Erythromycin , 1994, The Annals of pharmacotherapy.

[62]  J. Lin,et al.  Kinetic studies on the deethylation of ethoxybenzamide. A comparative study with isolated hepatocytes and liver microsomes of rat. , 1980, Biochemical pharmacology.

[63]  R. Elofsson,et al.  Binding of two adrenergic beta-receptor antagonists, alprenolol and H 93-26, to human serum proteins. , 1974, Acta pharmaceutica Suecica.

[64]  K. Bischoff,et al.  Methotrexate pharmacokinetics. , 1971, Journal of pharmaceutical sciences.

[65]  L. Bass,et al.  Physiologically based models and strategic experiments in hepatic pharmacology. , 1988, Biochemical pharmacology.

[66]  G. de Sousa,et al.  Interspecies variability in mitoxantrone metabolism using primary cultures of hepatocytes isolated from rat, rabbit and humans. , 1991, Biochemical pharmacology.

[67]  G L Amidon,et al.  The influence of the interdigestive migrating myoelectric complex on the gastric emptying of liquids. , 1990, Gastroenterology.

[68]  F. Guengerich,et al.  Differential inhibition of individual human liver cytochromes P-450 by cimetidine. , 1991, Gastroenterology.

[69]  A. Rane,et al.  Morphine glucuronidation in the rhesus monkey: a comparative in vivo and in vitro study. , 1984, The Journal of pharmacology and experimental therapeutics.

[70]  G R Wilkinson,et al.  Clearance approaches in pharmacology. , 1987, Pharmacological reviews.

[71]  J. Lin,et al.  Species similarities and differences in pharmacokinetics. , 1995, Drug metabolism and disposition: the biological fate of chemicals.

[72]  J. Miners,et al.  Characterisation of theophylline metabolism in human liver microsomes. , 1987, British journal of clinical pharmacology.

[73]  J S Harmatz,et al.  Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. , 1996, The Journal of pharmacology and experimental therapeutics.

[74]  T. Leemann,et al.  In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors , 1996, European Journal of Clinical Pharmacology.

[75]  K H Antonin,et al.  Pharmacokinetics and plasma binding of diazepam in man, dog, rabbit, guinea pig and rat. , 1976, The Journal of pharmacology and experimental therapeutics.

[76]  R. Chenery,et al.  Comparative drug metabolism of diazepam in hepatocytes isolated from man, rat, monkey and dog. , 1989, Biochemical pharmacology.

[77]  W. L. Nelson,et al.  Inhibition of the enantioselective oxidative metabolism of metoprolol by verapamil in human liver microsomes. , 1993, Drug metabolism and disposition: the biological fate of chemicals.

[78]  D. Greenblatt,et al.  Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. , 1995, Journal of clinical psychopharmacology.

[79]  P. Beaune,et al.  Identification of the cytochrome P450 IIIA family as the enzymes involved in the N-demethylation of tamoxifen in human liver microsomes. , 1991, Biochemical pharmacology.

[80]  M. Bayliss,et al.  Prediction of intrinsic clearance of loxtidine from kinetic studies in rat, dog and human hepatocytes. , 1990, Biochemical Society transactions.

[81]  T Ishizaki,et al.  Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data. , 1997, Pharmacology & therapeutics.

[82]  P. Robinson,et al.  Hepatic elimination of flowing substrates: the distributed model. , 1978, Journal of theoretical biology.

[83]  Y. Sugiyama,et al.  Strategic proposals for avoiding toxic interactions with drugs for clinical use during development and after marketing of a new drug: pharmacokinetic consideration. , 1996, The Journal of toxicological sciences.