title: Assessment of cytochrome P450 3A4 activity during the menstrual cycle using alfentanil as a noninvasive probe.
abstract: BACKGROUND
  Gender-dependent differences in cytochrome P450 activity, drug metabolism, drug elimination, and their clinical consequences are increasingly apparent. P450 3A4 is the most abundant P450 isoform in the human liver and is responsible for metabolizing a vast and diverse assortment of therapeutic agents, including opioids, benzodiazepines, and local anesthetics. P450, 3A4 activity is higher in women, influenced by steroid hormone levels, and is speculated to vary during the menstrual cycle. This investigation tested the hypothesis that P450 3A4 activity varies during the menstrual cycle. Alfentanil clearance was used as a metabolic probe for P450 3A4 activity.
  
  
  METHODS
  Alfentanil (20 micrograms/kg bolus) was administered to nine nonsmoking, nonpregnant female volunteers (age, 26 +/- 5 yr) with normal menstrual cycles on three separate occasions during the same menstrual cycle: days 2 (menstrual phase), 13 (estrogen peak), and 21 (progesterone peak). Venous plasma alfentanil concentrations were determined by gas chromatography-mass spectrometry. Alfentanil clearance was determined by noncompartmental methods and by a three-compartment model with both pooled population and two-stage analysis.
  
  
  RESULTS
  There was no significant difference in any measure of alfentanil clearance. Noncompartmental clearances (mean +/- SD) were 3.62 +/- 0.76, 3.81 +/- 0.96, and 3.60 +/- 0.84 ml/kg/ min, respectively, on days 2, 13, and 21 of the menstrual cycle.
  
  
  CONCLUSIONS
  Alfentanil clearances were not different on menstrual cycle days 2, 13, and 21, strongly suggesting no change in P450 3A4 activity. Menstrual cycle differences in alfentanil clearances do not contribute to interindividual variability in alfentanil disposition in women. If other P450 3A4 substrates are comparable, then menstrual cycle variability in their metabolism may not be a consideration in dosing or in the design of pharmacokinetic investigations.
authors.affiliation: Anesthesiology Service, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA. kharasch@u.washington.edu
authors.forename: E D
authors.initials: ED
authors.lastname: Kharasch
authors.forename: M
authors.initials: M
authors.lastname: Russell
authors.forename: K
authors.initials: K
authors.lastname: Garton
authors.forename: G
authors.initials: G
authors.lastname: Lentz
authors.forename: T A
authors.initials: TA
authors.lastname: Bowdle
authors.forename: K
authors.initials: K
authors.lastname: Cox
mesh_terms: D000293:Adolescent; D000328:Adult; D015760:Alfentanil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D008598:Menstruation / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D018686:Anesthetics, Intravenous; D015760:Alfentanil; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A