Gender Has a Small but Statistically Significant Effect on Clearance of CYP3A Substrate Drugs

The role of gender on the disposition of drugs metabolized by cytochrome P4503A (CYP3A) remains controversial. Some sources suggest that CYP3A activity in women exceeds that in men, but evidence to support this position is inconsistent at best. We evaluated 38 data sets in which clearance of CYP3A substrate drugs was studied in healthy young male and young female subjects. None of these drugs was a substrate for transport by P‐glycoprotein (P‐gp). The overall mean (±SE) for the female/male ratio of weight‐normalized clearance was 1.26 (±0.07) for parenteral dosage and 1.17 (±0.07) for oral dosage. Both ratios were significantly different (P < .05) from 1.0. For oral dosage studies, the female/male clearance ratio was unrelated to the drug's absolute oral bioavailability. Thus gender has a small and statistically significant, although most likely clinically unimportant, influence on CYP3A phenotype for substrates not transported by P‐gp.

[1]  D. Greenblatt,et al.  Chapter 11:The CYP3 Family , 2008 .

[2]  R. Rosengren,et al.  Sex-specific differences in CYP450 isoforms in humans , 2008, Expert opinion on drug metabolism & toxicology.

[3]  J. Schwartz.  The Current State of Knowledge on Age, Sex, and Their Interactions on Clinical Pharmacology , 2007, Clinical pharmacology and therapeutics.

[4]  G. Drusano,et al.  Sex differences in CYP3A activity using intravenous and oral midazolam , 2006, Clinical pharmacology and therapeutics.

[5]  D. Greenblatt,et al.  FACTORS INFLUENCING MIDAZOLAM HYDROXYLATION ACTIVITY IN HUMAN LIVER MICROSOMES , 2006, Drug Metabolism and Disposition.

[6]  Mei-ling Chen.  Confounding factors for sex differences in pharmacokinetics and pharmacodynamics: Focus on dosing regimen, dosage form, and formulation , 2005, Clinical pharmacology and therapeutics.

[7]  J. Kaiser.  Gender in the Pharmacy: Does It Matter? , 2005, Science.

[8]  Shiew-Mei Huang,et al.  DO MEN AND WOMEN DIFFER IN PROXIMAL SMALL INTESTINAL CYP3A OR P-GLYCOPROTEIN EXPRESSION? , 2005, Drug Metabolism and Disposition.

[9]  G. Anderson.  Sex and racial differences in pharmacological response: where is the evidence? Pharmacogenetics, pharmacokinetics, and pharmacodynamics. , 2005, Journal of women's health.

[10]  D. Greenblatt,et al.  The Influence of Age and Sex on the Clearance of Cytochrome P450 3A Substrates , 2005, Clinical Pharmacokinetics.

[11]  Alfred A Cecchetti,et al.  Bioequivalence revisited: Influence of age and sex on CYP enzymes , 2004, Clinical pharmacology and therapeutics.

[12]  K. Carroll,et al.  The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes. , 2004, Toxicology and applied pharmacology.

[13]  Peter Neuhaus,et al.  Sex is a major determinant of CYP3A4 expression in human liver , 2003, Hepatology.

[14]  D. Greenblatt,et al.  Pharmacokinetic properties of zolpidem in elderly and young adults: possible modulation by testosterone in men. , 2003, British journal of clinical pharmacology.

[15]  W. Ambrosius,et al.  The effect of age, sex, and rifampin administration on intestinal and hepatic cytochrome P450 3A activity , 2003, Clinical pharmacology and therapeutics.

[16]  D. Ciraulo.  Neuropsychopharmacology: The Fifth Generation of Progress , 2003 .

[17]  Zhaoqian Liu,et al.  The distribution and gender difference of CYP3A activity in Chinese subjects. , 2003, British journal of clinical pharmacology.

[18]  E. Kharasch,et al.  Gender differences in drug effects: implications for anesthesiologists , 2003, Acta anaesthesiologica Scandinavica.

[19]  J. Dorne,et al.  Human variability in CYP3A4 metabolism and CYP3A4-related uncertainty factors for risk assessment. , 2003, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[20]  L. Benet,et al.  Sex‐related differences in the clearance of cytochrome P450 3A4 substrates may be caused by P‐glycoprotein , 2002, Clinical pharmacology and therapeutics.

[21]  J. Schwartz,et al.  Race and sex influence clearance of nifedipine: Results of a population study , 2000, Clinical pharmacology and therapeutics.

[22]  A. Nafziger,et al.  Is it sex or is it gender? , 2000, Clinical pharmacology and therapeutics.

[23]  D. Greenblatt,et al.  Comparative kinetics and response to the benzodiazepine agonists triazolam and zolpidem: evaluation of sex-dependent differences. , 2000, The Journal of pharmacology and experimental therapeutics.

[24]  D. Greenblatt,et al.  Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: Effect of ketoconazole , 1999, Clinical pharmacology and therapeutics.

[25]  A. Holdcroft,et al.  Drugs and sex differences: a review of drugs relating to anaesthesia. , 1999, British journal of anaesthesia.

[26]  A. Kashuba,et al.  Quantification of 3‐month intraindividual variability and the influence of sex and menstrual cycle phase on CYP3A activity as measured by phenotyping with intravenous midazolam , 1998, Clinical pharmacology and therapeutics.

[27]  J. Gorski,et al.  The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin , 1998, Clinical pharmacology and therapeutics.

[28]  G. L. Kedderis,et al.  Sex-dependent metabolism of xenobiotics. , 1998, Drug metabolism reviews.

[29]  Morton B. Brown,et al.  Role of intestinal P‐glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine , 1997, Clinical pharmacology and therapeutics.

[30]  E. Kharasch,et al.  The Role of Cytochrome P450 3A4 in Alfentanil Clearance: Implications for Interindividual Variability in Disposition and Perioperative Drug Interactions , 1997, Anesthesiology.

[31]  E. Kharasch,et al.  Assessment of Cytochrome P450 3A4 Activity during the Menstrual Cycle Using Alfentanil as a Noninvasive Probe , 1997, Anesthesiology.

[32]  G. Wilkinson.  Cytochrome P4503A (CYP3A) metabolism: Prediction ofIn Vivo activity in humans , 1996, Journal of Pharmacokinetics and Biopharmaceutics.

[33]  J. Kuhlmann,et al.  The influence of age on the pharmacokinetics of nimodipine. , 1996, International journal of clinical pharmacology and therapeutics.

[34]  D. Shen,et al.  Oral first‐pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A‐mediated metabolism , 1996, Clinical pharmacology and therapeutics.

[35]  U. Gundert-Remy,et al.  Gender differences in pharmacokinetics , 1996, European Journal of Drug Metabolism and Pharmacokinetics.

[36]  R. Barbhaiya,et al.  A study of the effect of age and gender on the pharmacokinetics of nefazodone after single and multiple doses. , 1996, Journal of clinical psychopharmacology.

[37]  K. Byth,et al.  Age but not gender selectively affects expression of individual cytochrome P450 proteins in human liver. , 1995, Biochemical pharmacology.

[38]  P. Kroboth,et al.  Triazolam pharmacokinetics after intravenous, oral, and sublingual administration. , 1995, Journal of clinical psychopharmacology.

[39]  H. Yamazaki,et al.  Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. , 1994, The Journal of pharmacology and experimental therapeutics.

[40]  D. Greenblatt,et al.  Distinguishing a benzodiazepine agonist (triazolam) from a nonagonist anxiolytic (buspirone) by electroencephalography: Kinetic‐dynamic studies , 1994, Clinical pharmacology and therapeutics.

[41]  P. Ward,et al.  Effect of age and gender on tirilazad pharmacokinetics in humans , 1994, Clinical pharmacology and therapy.

[42]  L. K. Hulst,et al.  Pharmacokinetics and Pharmacodynamics of Adinazolam and N‐Desmethyladinazolam after Oral and Intravenous Dosing in Healthy Young and Elderly Volunteers , 1992, Journal of Clinical Psychopharmacology.

[43]  C. Hunt,et al.  Effect of age and gender on the activity of human hepatic CYP3A. , 1992, Biochemical pharmacology.

[44]  K. Yonkers,et al.  Gender differences in pharmacokinetics and pharmacodynamics of psychotropic medication. , 1992, The American journal of psychiatry.

[45]  C. DeVane,et al.  Influence of menstrual cycle and gender on alprazolam pharmacokinetics , 1991, Clinical pharmacology and therapeutics.

[46]  H. Wynne,et al.  Effects of age and gender on in vitro properties of human liver microsomal monooxygenases , 1990, Clinical pharmacology and therapeutics.

[47]  J. P. Shea,et al.  Pharmacokinetics of Buspirone in Elderly Subjects , 1989, Journal of clinical pharmacology.

[48]  I. Patel,et al.  Effects of Age, Gender and Oral Contraceptives on Intramuscular Midazolam Pharmacokinetics , 1988, Journal of clinical pharmacology.

[49]  A. Burm,et al.  Influence of Age on the Pharmacokinetics of Alfentanil , 1988, Clinical pharmacokinetics.

[50]  D. Greenblatt,et al.  Trazodone kinetics: Effect of age, gender, and obesity , 1987, Clinical pharmacology and therapeutics.

[51]  D. Greenblatt,et al.  Bromazepam pharmacokinetics: Influence of age, gender, oral contraceptives, cimetidine, and propranolol , 1987, Clinical pharmacology and therapeutics.

[52]  D. Greenblatt,et al.  Effect of Age, Gender, and Obesity on Midazolam Kinetics , 1984, Anesthesiology.

[53]  D. Greenblatt,et al.  Effect of subject age and gender on the pharmacokinetics of oral triazolam and temazepam. , 1983, Journal of clinical psychopharmacology.

[54]  D. Greenblatt,et al.  Alprazolam kinetics in the elderly. Relation to antipyrine disposition. , 1983, Archives of general psychiatry.

[55]  D. Greenblatt,et al.  Reduced clearance of triazolam in old age: relation to antipyrine oxidizing capacity. , 1983, British journal of clinical pharmacology.

[56]  D. Greenblatt,et al.  Clobazam kinetics in the elderly. , 1981, British journal of clinical pharmacology.

[57]  D. Mattison,et al.  Sex Differences in Pharmacokinetics and Pharmacodynamics , 2009, Clinical pharmacokinetics.

[58]  P. Thuermann.  Gender-differences in pharmacokinetics and pharmacodynamics , 2006 .

[59]  M. Kendall,et al.  The intra- and inter-subject variability of Nifedipine pharmacokinetics in young volunteers , 2004, European Journal of Clinical Pharmacology.

[60]  L. Wojnowski,et al.  Cytochrome P450 3A and their regulation , 2004, Naunyn-Schmiedeberg's Archives of Pharmacology.

[61]  J. Schwartz.  The Influence of Sex on Pharmacokinetics , 2003, Clinical pharmacokinetics.

[62]  Hartmut Derendorf,et al.  How Important Are Gender Differences in Pharmacokinetics? , 2002, Clinical pharmacokinetics.

[63]  F. Guengerich,et al.  Cytochrome P-450 3A4: regulation and role in drug metabolism. , 1999, Annual review of pharmacology and toxicology.

[64]  B. Pollock.  Gender differences in psychotropic drug metabolism. , 1997, Psychopharmacology bulletin.

[65]  P. Beaune,et al.  Interindividual variability in catalytic activity and immunoreactivity of three major human liver cytochrome P450 isozymes , 1996, European Journal of Clinical Pharmacology.

[66]  F. Kristjánsson,et al.  Disposition of alprazolam in human volunteers. Differences between genders. , 1991, Acta pharmaceutica Nordica.

[67]  W. Potter,et al.  Gender differences in pharmacokinetics and pharmacodynamics of psychotropics: focus on women. , 1991, Psychopharmacology bulletin.