CYTOCHROME P 450 INVOLVEMENT IN THE BIOTRANSFORMATION OF CISAPRIDE AND RACEMIC NORCISAPRIDE IN VITRO : DIFFERENTIAL ACTIVITY OF INDIVIDUAL HUMAN CYP 3 A ISOFORMS
CYTOCHROME P 450 INVOLVEMENT IN THE BIOTRANSFORMATION OF CISAPRIDE AND RACEMIC NORCISAPRIDE IN VITRO : DIFFERENTIAL ACTIVITY OF INDIVIDUAL HUMAN CYP 3 A ISOFORMS
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细胞色素 P 450 参与西沙必利和外消旋诺西必利的体外生物转化：个体人类 CYP 3 A 异构体的差异活性
DOI：
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
J. Leeder
中科院分区：
文献类型：
--
作者：
R. Pearce;R. Gotschall;G. Kearns;J. Leeder
Identification of the human cytochrome P450 (P450) enzymes involved in the metabolism of cisapride and racemic norcisapride [( )-norcisapride] was investigated at 0.1 and 1 M, concentrations that span the mean plasma Cmax for cisapride. Formation of norcisapride (Nor), 3-fluoro-4-hydroxycisapride (3F), and 4-fluoro2-hydroxycisapride (4F) from cisapride and an uncharacterized metabolite (UNK) from ( )-norcisapride in human liver microsomes (HLMs) were consistent with Michaelis-Menten kinetics for a single enzyme (Km, 6.0, 14.3, 13.9, and 107 M; Vmax, 1350, 696, 568, and 25 pmol/mg of protein, respectively). HLMs converted cisapride to Nor at rates that were at least 3 orders of magnitude greater than those observed for ( )-norcisapride conversion to UNK. The sample-to-sample variation in the rates of Nor, 3F, 4F, and UNK formation correlated strongly (r > 0.796) with CYP3A4/5 activity in a panel of HLMs (n 7) and was markedly reduced by ketoconazole, a potent CYP3A inhibitor. Ketoconazole virtually eliminated ( )norcisapride conversion to UNK (94 0.5%). Studies with 10 cDNA-expressed enzymes revealed that CYP3A4 catalyzed the formation of Nor and 4F at rates >100 times those of non-CYP3A enzymes and >100and 50-fold higher than CYP3A5 and CYP3A7, respectively. CYP3A4 was the only P450 capable of UNK formation. Therefore, CYP3A4 is the principal P450 enzyme responsible for the conversion of cisapride to Nor, 3F, and 4F and of ( )-norcisapride to UNK. Compared with cisapride, factors related to CYP3A4mediated ( )-norcisapride metabolism (e.g., ontogeny of drugmetabolizing enzymes, inhibition, and induction) should be clinically unimportant due to the apparent lack of dependence on cytochromes P450 for elimination. Cisapride is a prokinetic drug that acts as a postganglionic serotonin 5-hydroxytryptamine receptor agonist (McCallum et al., 1988). It has been widely used in adults and children for the treatment of gastroparesis and symptoms associated with gastroesophageal reflux disease (Wiseman and Faulds, 1994; Vandenplas, 1998). Cisapride has also been administered frequently to neonates and young infants to facilitate oral feeding and to reduce the potential for severe adverse effects (e.g., apnea and bradycardia) associated with excessive regurgitation of gastric contents (Enriquez et al., 1998; Vandenplas, 1998). Cisapride is a well tolerated drug with a low incidence (i.e., approximately 2%) of adverse effects that are predominantly gastrointestinal in nature (Vandenplas et al., 1999). In rare cases, cisapride has been linked to prolonged QTc intervals and the production of potentially life-threatening ventricular arrhythmias (Lewin et al., 1996; van Haarst et al., 1998). Cardiac side effects have been most commonly reported in individuals receiving accidental overdoses of cisapride or in cases in which cisapride was coadministered with other drugs that alter cisapride clearance (e.g., CYP3A inhibitors) and/or prolong QTc intervals through effects on the iKr channel (e.g., azole antifungals, erythromycin, and clarithromycin) (Michalets and Williams, 2000). Safety concerns related to the association of these rare, cardiac side effects with cisapride administration prompted a recent, voluntary withdrawal of cisapride from the U.S. market by the man-
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DOI：
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发表时间：
1994-07
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
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作者：
T. Shimada;H. Yamazaki;M. Mimura;Y. Inui;F. Guengerich
通讯作者：
T. Shimada;H. Yamazaki;M. Mimura;Y. Inui;F. Guengerich
兰索拉唑代谢中涉及的人类 P450 酶的鉴定。
DOI：
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发表时间：
1996
期刊：
The Journal of pharmacology and experimental therapeutics.
影响因子：
--
作者：
Pearce,RE;Rodrigues,AD;Goldstein,JA;Parkinson,A
通讯作者：
Parkinson,A
鉴定负责 S-甲基 N,N-二乙基硫醇氨基甲酸酯 (DETC-ME) 磺化氧化的人和大鼠 P450 酶。
DOI：
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发表时间：
1995
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
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作者：
Madan,A;Parkinson,A;Faiman,MD
通讯作者：
Faiman,MD
DOI：
10.1097/00008571-199402000-00002
发表时间：
1994-02-01
期刊：
PHARMACOGENETICS
影响因子：
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作者：
SCHUETZ, JD;BEACH, DL;GUZELIAN, PS
通讯作者：
GUZELIAN, PS
西沙必利与人细胞色素 P450 系统的相互作用：代谢和抑制研究。
DOI：
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发表时间：
2000
期刊：
Drug metabolism and disposition: the biological fate of chemicals.
影响因子：
--
作者：
Desta,Z;Soukhova,N;Mahal,SK;Flockhart,DA
通讯作者：
Flockhart,DA