QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.105.007997v1 34/6/950    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shimizu, T. Articles by Chiba, K. Search for Related Content PubMed PubMed Citation Articles by Shimizu, T. Articles by Chiba, K.

AUTOINDUCTION OF MKC-963 [(R)-1-(1-CYCLOHEXYLETHYLAMINO)-4-PHENYLPHTHALAZINE] METABOLISM IN HEALTHY VOLUNTEERS AND ITS RETROSPECTIVE EVALUATION USING PRIMARY HUMAN HEPATOCYTES AND CDNA-EXPRESSED ENZYMES

Pharmacokinetics Laboratory, Mitsubishi Pharma Corporation, Chiba, Kisarazu-shi, Japan (T.S., K.A., T.Y. and T.N.); Hohsen Clinic, Research Center for Clinical Pharmacology, The Kitasato Institute, Tokyo, Japan (M.T.); and Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (T.S., K.K. and K.C.)

MKC-963, (R)-1-(1-cyclohexylethylamino)-4-phenylphthalazine, a potent inhibitor of platelet aggregation, was synthesized and used in clinical trials in the 1990s. In the process of clinical study, it was found that urinary excretion ratios for 6ß-hydroxycortisol and free cortisol increased significantly in parallel with decreases in the plasma concentrations of MKC-963 after repeated oral administration of the compound to healthy volunteers. These findings suggested that MKC-963 caused autoinduction (defined as the ability of a drug to induce enzymes that enhance its own metabolism, resulting in dispositional tolerance) in humans, and clinical studies using the compound were stopped. This experience prompted us to reevaluate the effects of this compound on CYP3A4 using primary human hepatocytes and cDNA-expressed human cytochrome P450 (P450) enzymes to determine whether the autoinduction of MKC-963 metabolism in humans could have been predicted if these in vitro systems had been used for the evaluation of MKC-963 in the preclinical study. The results of in vitro study showed that MKC-963 increased CYP3A4 mRNA expression level and activity of testosterone 6ß-hydroxylation to extents similar to those observed with rifampicin in primary human hepatocytes. In addition, approximately 90% of the MKC-963 metabolism in human liver microsomes was estimated to be attributable to CYP3A4. These in vitro findings are in good agreement with the results of clinical study, suggesting that studies using human hepatocytes and cDNA-expressed human P450s are useful for assessing the autoinductive nature of compounds under development before starting clinical studies.

This article has been cited by other articles:

				C. Tang, B. A. Carr, F. Poignant, B. Ma, S. L. Polsky-Fisher, Y. Kuo, K. Strong-Basalyga, A. Norcross, K. Richards, R. Eisenhandler, et al. CYP2C75-Involved Autoinduction of Metabolism in Rhesus Monkeys of Methyl 3-Chloro-3'-fluoro-4'-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-1,1'-biphenyl-2-carboxylate (MK-0686), a Bradykinin B1 Receptor Antagonist J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 935 - 946. [Abstract] [Full Text] [PDF]

				R. Kitamura, Y. Yamamoto, S. Nagayama, and M. Otagiri Decrease in Plasma Concentrations of Antiangiogenic Agent TSU-68 ((Z)-5-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid) during Oral Administration Twice a Day to Rats Drug Metab. Dispos., September 1, 2007; 35(9): 1611 - 1616. [Abstract] [Full Text] [PDF]