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EFFECTS OF ENDOGENOUS STEROIDS ON CYP3A4-MEDIATED DRUG METABOLISM ...
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Short Description: Effects of Various Endogenous Steroids on Drug Metabolism. .... where drugs are mainly metabolized. Thus, drug-endogenous steroid ...
Content Inside: 0090-9556/02/3005-534540$7.00 DRUG METABOLISM AND DISPOSITION Vol. 30, No. 5 Copyright 2002 by The American Society for Pharmacology and Experimental Therapeutics 582/977211 DMD 30:534540, 2002 Printed in U.S.A. EFFECTS OF ENDOGENOUS STEROIDS ON CYP3A4-MEDIATED DRUG METABOLISM BY HUMAN LIVER MICROSOMES HIROYOSHI NAKAMURA, HIROMITSU NAKASA, ITSUKO ISHII, NORITAKA ARIYOSHI, TAKASHI IGARASHI, SHIGERU OHMORI, AND MITSUKAZU KITADA Division of Pharmacy, Chiba University Hospital, Chuo-ku, Chiba, Japan (H.Nakam., H.Nakas., N.A., M.K.); Graduate School of Pharmaceutical Science, Chiba University, Inage-ku, Chiba, Japan (I.I.); Drug Metabolism and Pharmacokinetics, Kawanishi Pharma Research Institute, Nippon Boehringer Ingelheim Company, Kawanishi, Hyougo, Japan (T.I.); and Division of Pharmacy, Shinsyu University Hospital, Matsumoto, Japan (S.O.) (Received September 14, 2001; accepted January 30, 2002) This article is available online at http://dmd.aspetjournals.org ABSTRACT: In the present study, we investigated the effects of 14 endogenous sis of the metabolism of CBZ and ZNS in the presence or absence Downloaded from steroids on the CYP3A4-mediated drug metabolism by human liver of AND using the modified two-site equation model. The addition of microsomes in vitro. Nevirapine (NVP) 2-, 12-hydroxylations, car- AND to the reaction mixture caused a drastic increase in the bamazepine (CBZ) 10,11-epoxidation, triazolam (TZM) 1 -, 4-hy- activity of CBZ 10,11-epoxidase, especially at a low substrate con- droxylations, erythromycin (EM) N-demethylation, and 2-sulpha- centration, and resulted in a change in the kinetics from the sig- moylacetylphenol (SMAP) formation from zonisamide (ZNS) were moid to Michaelis-Menten type. On the other hand, the metabolism investigated. The activities of the NVP 2-, 12-hydroxylations, the of ZNS was strongly inhibited by AND, although no allosteric dmd.aspetjournals.org CBZ 10,11-epoxidation, and the TZM 4-hydroxylation were acti- change was observed in this case. These data demonstrate that vated by endogenous androgens, such as androstenedione (AND), endogenous steroids, especially androgens, strongly affect testosterone, and dehydroepiandrosterone. However, these an- CYP3A4-mediated drug metabolism in vitro. The postulated mech- drogens inhibited EM N-demethylation, TZM 1 -hydroxylation, and anisms of the interactions between AND and CBZ or ZNS are SMAP formation. To understand the mechanisms of these effects discussed. of androgens on CYP3A4 activities, we performed a kinetic analy- by on December 25, 2008 Cytochrome P450s (P450s1) are comprised of a superfamily of thoflavone heterotropically stimulates the metabolism of progester- enzymes that play important roles in drug metabolism. CYP3A4 is one, testosterone (Schwab et al., 1988; Harlow and Halpert, 1998), known to be a major form of P450 expressed in adult human livers and various other CYP3A substrates (Andersson et al., 1994), provid- (Shimada et al., 1994), and a majority of the drugs currently available ing a change in the kinetic character to the Michaelis-Menten type. on the market are metabolized by this isoform (Maurel, 1996). The active site in CYP3A4 is generally supposed to be spacious CYP3A4 is also responsible for the metabolism of endogenous com- because CYP3A4 can metabolize relatively large molecules, such as pounds, such as steroid hormones. It has been reported that CYP3A4 cyclosporin (mol. wt., 1201). In contrast to the model for a single is involved in the metabolism of cortisol (Abel and Back, 1993), large active site, another model possessing two binding sites at the testosterone (Waxman et al., 1988), estradiol-17 (Kerlan et al., active site of a P450 has been suggested (Shou et al., 1994). Several 1992), and progesterone (Yamazaki and Shimada, 1997), all of which kinetic analyses based on the latter hypothesis have been reported play important roles in various physiological actions. (Korzekwa et al., 1998; Shou et al., 2001). Several reactions catalyzed by CYP3A4 display non-Michaelis- Since many endogenous steroids are recognized to be substrates of Menten kinetics, apparently due to an allosteric effect, which com- CYP3A4, these endogenous steroids may competitively inhibit drug monly yields a sigmoid velocity saturation curve. For example, a metabolism catalyzed by CYP3A4. However, a recent article has sigmoid kinetic character has been observed for the metabolism of indicated that testosterone activates the metabolism of midazolam CBZ (Kerr et al., 1994; Korzekwa et al., 1998), progesterone (Harlow 4-hydroxylation by human liver microsomes (Maenpaa et al., 1998). and Halpert, 1998), and testosterone (Ueng et al., 1997; Harlow and Another study showed that testosterone activates the TZM 4-hydroxy- Halpert, 1998) by CYP3A4. In addition, it is well known that -naph- lation but inhibits 1 -hydroxylation by human liver microsomes 1 (Schrag and Wienkers, 2001). Thus, the effects of testosterone on Abbreviations used are: P450, cytochrome P450; CBZ, carbamazepine; TZM, triazolam; NVP, nevirapine; EM, erythromycin; SMAP, 2-sulphamoylacetyl- CYP3A4 activities seem to be complicated. phenol; AND, androstenedione; DHEA, dehydroepiandrosterone; ZNS, zoni- Because endogenous steroids always exist in vivo, it is of interest samide; HPLC, high-pressure liquid chromatography. to clarify the effects of endogenous steroids on drug metabolism mediated by CYP3A4. If endogenous steroids substantially affect Address correspondence to: Dr. Mitsukazu Kitada, Division of Pharmacy, CYP3A4 activities, it may be insufficient to estimate drug metabolism Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan. by CYP3A4 without considering the effects of endogenous steroids. E-mail: kitada@ho.chiba-u.ac.jp In this study, we focused on the effects of endogenous steroids on 534
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