Inhibitory effect of medroxyprogesterone acetate on human liver cytochrome P450 enzymes. 2006

Jiang-Wei Zhang, and Yong Liu, and Wei Li, and Da-Cheng Hao, and Ling Yang
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, People's Republic of China.

OBJECTIVE Medroxyprogesterone acetate (MPA), frequently used in contraception and chemotherapy, was involved in a report of drug-drug interaction (DDI) when co-administrated with phenytoin, doxifluridine and cyclophosphamide. In order to clarify the mechanism of such interaction, an in vitro study was undertaken to evaluate MPA's potential to inhibit cytochrome P450 (CYP) enzymes. METHODS Inhibitory effects of MPA on seven CYPs, including CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, CYP2E1 and CYP3A4, were conducted in human liver microsomes. Time- and NADPH-dependent inhibitions were also tested. DDI potential was predicted according to the [I]/K ( i ) value. RESULTS MPA was found to inhibit CYP2C9 and CYP3A4; half inhibition concentration (IC(50)) was 16.1 microM and 31.5 microM, respectively. Slight inhibition was observed on CYP1A2, CYP2A6, CYP2C8 and CYP2D6 with IC(50) of more than 100 microM. MPA exhibited activation rather than inhibition on CYP2E1. Further study revealed that MPA showed a noncompetitive inhibition on CYP2C9 and a competitive inhibition on CYP3A4 with K ( i ) of 9.0 microM and 36 microM, respectively. In addition, MPA was not a mechanism-based inhibitor to any of seven isoforms tested. By using predicted concentration of MPA in liver, [I]/K ( i ) was estimated to be 0.24 and 0.06 for CYP2C9 and CYP3A4, respectively. The concentration of phenytoin co-administrated with MPA was calculated to increase by 24%. CONCLUSIONS Based on our results, MPA can possibly cause clinically relevant DDI via the inhibition of CYP2C9.

UI MeSH Term Description Entries
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D008297 Male Males
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D003577 Cytochrome P-450 Enzyme System A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism. Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D004008 Diclofenac A non-steroidal anti-inflammatory agent (NSAID) with antipyretic and analgesic actions. It is primarily available as the sodium salt. Diclophenac,Dichlofenal,Diclofenac Potassium,Diclofenac Sodium,Diclonate P,Dicrofenac,Feloran,GP-45,840,Novapirina,Orthofen,Orthophen,Ortofen,SR-38,Sodium Diclofenac,Voltaren,Voltarol,Diclofenac, Sodium,GP 45,840,GP45,840,SR 38,SR38
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006900 Hydroxylation Placing of a hydroxyl group on a compound in a position where one did not exist before. (Stedman, 26th ed) Hydroxylations
D000328 Adult A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available. Adults
D013739 Testosterone A potent androgenic steroid and major product secreted by the LEYDIG CELLS of the TESTIS. Its production is stimulated by LUTEINIZING HORMONE from the PITUITARY GLAND. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to DIHYDROTESTOSTERONE or ESTRADIOL. 17-beta-Hydroxy-4-Androsten-3-one,17-beta-Hydroxy-8 alpha-4-Androsten-3-one,8-Isotestosterone,AndroGel,Androderm,Andropatch,Androtop,Histerone,Sterotate,Sustanon,Testim,Testoderm,Testolin,Testopel,Testosterone Sulfate,17 beta Hydroxy 4 Androsten 3 one,17 beta Hydroxy 8 alpha 4 Androsten 3 one,8 Isotestosterone
D017258 Medroxyprogesterone Acetate A synthetic progestin that is derived from 17-hydroxyprogesterone. It is a long-acting contraceptive that is effective both orally or by intramuscular injection and has also been used to treat breast and endometrial neoplasms. Depo-Medroxyprogesterone Acetate,Medroxyprogesterone 17-Acetate,Pregn-4-ene-3,20-dione, 17-(acetyloxy)-6-methyl-, (6alpha)-,(6 alpha)-17-(Acetoxy)-6-methylpregn-4-ene-3,20-dione,6-alpha-Methyl-17alpha-hydroxyprogesterone Acetate,Curretab,Cycrin,Depo-Provera,Farlutal,Gestapuran,Medroxyprogesterone 17-Acetate, (6 alpha,17 alpha)-Isomer,Medroxyprogesterone 17-Acetate, (6 beta)-Isomer,Perlutex,Provera,Veramix,6 alpha Methyl 17alpha hydroxyprogesterone Acetate,Depo Medroxyprogesterone Acetate,Depo Provera,DepoProvera,Medroxyprogesterone 17 Acetate

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