Race and sex influence clearance of nifedipine: Results of a population study

Krecic‐Shepard, Mary Ellen; Park, Kyungsoo; Barnas, C.; Slimko, Jill; Kerwin, Diana; Schwartz, Janice B.

doi:10.1067/mcp.2000.108678

Cited by 92 publications

(66 citation statements)

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“…Gender differences in expression of cytochrome P450 were not statistically significant except in the case of CYP3A4, in line with literature on CYP3A4 abundance (Wolbold et al, 2003). This finding is supported by reports of more efficient clearance of CYP3A substrates, such as nifedipine (Krecic-Shepard et al, 2000), verapamil (Wolbold et al, 2003), and cyclosporine (Kahan et al, 1986), in female subjects. CYP3A4 is highly inducible, and only one study (Wolbold et al, 2003) has distinguished between inducer-exposed and control subjects.…”

supporting

confidence: 80%

Expression of Hepatic Drug-Metabolizing Cytochrome P450 Enzymes and Their Intercorrelations: A Meta-Analysis

Achour

Barber

Rostami‐Hodjegan

2014

Drug Metabolism and Disposition

196

148

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Cytochrome P450 is a family of enzymes that catalyze reactions involved in the metabolism of drugs and other xenobiotics. These enzymes are therefore important in pharmacologic and toxicologic studies, and information on their abundances is of value in the process of scaling in vitro data to in vivo metabolic parameters. A meta-analysis was applied to data on the abundance of human hepatic cytochrome P450 enzymes in Caucasian adult livers (50 studies). Despite variations in the methods used to measure the abundance of enzymes, agreement between the studies in 26 different laboratories was generally good. Nonetheless, some heterogeneity was detected (Higgins and Thompson heterogeneity test). More importantly, large interindividual variability was observed in the collated data. Positive correlations between the expression levels of some cytochrome P450 enzymes were found in the abundance data, including the following pairs: CYP3A4/CYP3A5*1/*3 (Rs = 0.70, P < 0.0001, n = 52), CYP3A4/CYP2C8 (Rs = 0.68, P < 0.0001, n = 134), CYP3A4/CYP2C9 (Rs = 0.55, P < 0.0001, n = 71), and CYP2C8/CYP2C9 (Rs = 0.55, P < 0.0001, n = 99). These correlations can be used to demonstrate common genetic transcriptional mechanisms.

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supporting

confidence: 80%

Expression of Hepatic Drug-Metabolizing Cytochrome P450 Enzymes and Their Intercorrelations: A Meta-Analysis

Achour

Barber

Rostami‐Hodjegan

2014

Drug Metabolism and Disposition

196

148

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“…In this fictive sample of 40 men and 40 women, the sex difference in clearance rate is both significant ( p , 0.01) and of medium size (d ¼ 0.60). The effect size exceeds that for some real drugs, for example, cyclosporine and nifedipine, for which clearance rate differs significantly between the sexes [77,78]. The low p-value and medium effect size for Dimorphinil suggest non-trivial, clinically relevant sex difference [79].…”

Section: Pink Hippocampus Blue Hippocampus? Most Are Purplementioning

confidence: 99%

Perils and pitfalls of reporting sex differences

Maney¹

2016

Phil. Trans. R. Soc. B

134

104

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The idea of sex differences in the brain both fascinates and inflames the public. As a result, the communication and public discussion of new findings is particularly vulnerable to logical leaps and pseudoscience. A new US National Institutes of Health policy to consider both sexes in almost all preclinical research will increase the number of reported sex differences and thus the risk that research in this important area will be misinterpreted and misrepresented. In this article, I consider ways in which we might reduce that risk, for example, by (i) employing statistical tests that reveal the extent to which sex explains variation, rather than whether or not the sexes 'differ', (ii) properly characterizing the frequency distributions of scores or dependent measures, which nearly always overlap, and (iii) avoiding speculative functional or evolutionary explanations for sex-based variation, which usually invoke logical fallacies and perpetuate sex stereotypes. Ultimately, the factor of sex should be viewed as an imperfect, temporary proxy for yet-unknown factors, such as hormones or sex-linked genes, that explain variation better than sex. As scientists, we should be interested in discovering and understanding the true sources of variation, which will be more informative in the development of clinical treatments.

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“…CYP3A4, the predominant cytochrome P450 catalyst of oxidative metabolism in human liver, is expressed at a higher protein and mRNA level in women than in men (Hunt et al, 1992;Wolbold et al, 2003;Diczfalusy et al, 2008). Accordingly, certain CYP3A4 drug substrates, including cyclosporine (Kahan et al, 1986), erythromycin (Austin et al, 1980), and nifedipine (Krecic-Shepard et al, 2000), show higher clearance rates in women. CYP3A4-catalyzed hepatic microsomal N-dechloroethylation of the anticancer drug ifosfamide is also more rapid in women, suggesting that women could be more susceptible to the neurotoxic side affects associated with this metabolic pathway (Schmidt et al, 2001).…”

Section: Sex Differences In Hepatic Drug Metabolismmentioning

confidence: 99%

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Waxman

Holloway²

2009

Molecular Pharmacology

634

584

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Sex differences in pharmacokinetics and pharmacodynamics characterize many drugs and contribute to individual differences in drug efficacy and toxicity. Sex-based differences in drug metabolism are the primary cause of sex-dependent pharmacokinetics and reflect underlying sex differences in the expression of hepatic enzymes active in the metabolism of drugs, steroids, fatty acids and environmental chemicals, including cytochromes P450 (P450s), sulfotransferases, glutathione transferases, and UDP-glucuronosyltransferases. Studies in the rat and mouse liver models have identified more than 1000 genes whose expression is sex-dependent; together, these genes impart substantial sexual dimorphism to liver metabolic function and pathophysiology. Sex differences in drug metabolism and pharmacokinetics also occur in humans and are due in part to the female-predominant expression of CYP3A4, the most important P450 catalyst of drug metabolism in human liver. The sexually dimorphic expression of P450s and other liver-expressed genes is regulated by the temporal pattern of plasma growth hormone (GH) release by the pituitary gland, which shows significant sex differences. These differences are most pronounced in rats and mice, where plasma GH profiles are highly pulsatile (intermittent) in male animals versus more frequent (nearly continuous) in female animals. This review discusses key features of the cell signaling and molecular regulatory mechanisms by which these sex-dependent plasma GH patterns impart sex specificity to the liver. Moreover, the essential role proposed for the GH-activated transcription factor signal transducer and activator of transcription (STAT) 5b, and for hepatic nuclear factor (HNF) 4␣, as mediators of the sexdependent effects of GH on the liver, is evaluated. Together, these studies of the cellular, molecular, and gene regulatory mechanisms that underlie sex-based differences in liver gene expression have provided novel insights into the physiological regulation of both xenobiotic and endobiotic metabolism.

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Race and sex influence clearance of nifedipine: Results of a population study

Cited by 92 publications

References 50 publications

Expression of Hepatic Drug-Metabolizing Cytochrome P450 Enzymes and Their Intercorrelations: A Meta-Analysis

Expression of Hepatic Drug-Metabolizing Cytochrome P450 Enzymes and Their Intercorrelations: A Meta-Analysis

Perils and pitfalls of reporting sex differences

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

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