Application of the PKCYP test to predict caffeine clearance mediated by CYP1A2 in a rat acute liver injury model.

We previously established a method for assessing in vivo drug-metabolizing capacity by pharmacokinetic estimation of the quantity of cytochrome P450 (CYP) in vivo (PKCYP test), in which an apparent liver-to-blood free concentration gradient in vivo (qg) is introduced (Matsunaga et al., Jpn. J. Hosp. Pharm., 26: 492-504 (2000)). This method was applied to estimate the amount of CYP2C11 in rats treated with carbon tetrachloride (CCl(4)-treated rats). In this study, we estimated the amount of CYP1A2 in CCl(4)-treated rats by using acetanilide and caffeine as a probe and a model drug, respectively. In CCl(4)-treated rats, the total body clearance (CL(tot)) of acetanilide and caffeine was about one-fifth and one-eighth of that in control rats, respectively. In CCl(4)-treated rats, the amount of CYP1A2 was predicted as 0.60+/-0.06 nmol/kg from the clearance of acetanilide mediated by CYP1A2. Moreover, the clearance of caffeine mediated by CYP1A2 in CCl(4)-treated rats was estimated as 0.47+/-0.05 mL/min/kg by using the predicted amount of CYP1A2. The observed value was 0.44+/-0.03 mL/min/kg, and the predicted value was within the 95% confidence interval of the observed value. In conclusion, we have demonstrated that the PKCYP test can also be applied for estimating the amount of CYP1A2 in CCl(4)-treated rats.

[1]  Magnus Ingelman-Sundberg,et al.  Polymorphism of cytochrome P450 and xenobiotic toxicity. , 2002, Toxicology.

[2]  R. Kim,et al.  Pharmacogenomics of organic anion-transporting polypeptides (OATP). , 2002, Advanced drug delivery reviews.

[3]  H. McLeod,et al.  Genetic basis of drug metabolism. , 2002, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[4]  E. Nakashima,et al.  Simultaneous assessment of the in vivo amount of CYP1A2 and CYP3A2 by the PKCYP-test using theophylline in rats. , 2002, Drug metabolism and pharmacokinetics.

[5]  H. Iizasa,et al.  Application of the PKCYP-test to predict the amount of in vivo CYP2C11 using tolbutamide as a probe. , 2001, Biological & pharmaceutical bulletin.

[6]  H. Iizasa,et al.  Application of the PKCYP-test in cases of altered CYP1A2 for multiple CYP systems in rat models of disease. , 2001, Biological & pharmaceutical bulletin.

[7]  U. Brinkmann,et al.  Polymorphisms in the ABC drug transporter gene MDR1 , 2001, The Pharmacogenomics Journal.

[8]  J. Villeneuve,et al.  Differential alteration of cytochrome P450 isoenzymes in two experimental models of cirrhosis. , 2000, Canadian journal of physiology and pharmacology.

[9]  M. Fukuhara,et al.  A Simplified Diagnostic Approach for Estimating in vivo Hepatic Drug Clearance. Its Preliminary Application for the Drug Caffeine, Using CYP1A Probe in a Rat Model.:Its Preliminary Application for the Drug Caffeine, Using CYP1A Probe in a Rat Model , 2000 .

[10]  A. Nafziger,et al.  Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. , 2000, Pharmacogenetics.

[11]  R. Obach,et al.  Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

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

[13]  E. Tanaka,et al.  Changes in the metabolism of three model substrates catalysed by different P450 isozymes when administered as a cocktail to the carbon tetrachloride-intoxicated rat. , 1995, Xenobiotica; the fate of foreign compounds in biological systems.

[14]  M. Fukuhara,et al.  Characterization of benzo[a]pyrene metabolism and related cytochrome P-450 isozymes in Syrian hamster livers. , 1995, Journal of toxicology and environmental health.

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

[16]  B. Ring,et al.  In vitro methods for assessing human hepatic drug metabolism: their use in drug development. , 1993, Drug metabolism reviews.

[17]  Fukuhara Morio,et al.  Aflatoxin B1-specific cytochrome P-450 isozyme (P-450-AFB) inducible by 3-methylcholanthrene in golden hamsters. , 1990 .

[18]  M. Ishidate,et al.  Characterization of three forms of cytochrome P-450 inducible by 3-methylcholanthrene in Golden hamster livers with special reference to aflatoxin B1 activation. , 1989, Journal of Biochemistry (Tokyo).

[19]  A. Tsuji,et al.  Effects of fasting on biperiden pharmacokinetics in the rat. , 1987, Journal of Pharmacy and Science.

[20]  K. Yamaoka,et al.  Moment analysis for disposition kinetics of several cephalosporin antibiotics in rats , 1983, The Journal of pharmacy and pharmacology.