title: Bioequivalence revisited: influence of age and sex on CYP enzymes.
abstract: OBJECTIVE
  The activity of cytochrome P450 (CYP) enzymes, which determine the rate of elimination of lipid-soluble drugs, demonstrates considerable interindividual variability. The extent to which age and sex influence CYP activity remains unclear in humans. Our objectives were to determine whether in vivo activity of selected CYP enzymes is affected by age or sex and to evaluate sex bioequivalence in a large sample size.
  
  
  METHODS
  We have assessed in vivo activity of the CYP1A2, 2C19, 2D6, 2E1, and 3A4 enzymes in 161 normal subjects (51% female subjects and 40% aged >50 years). After simultaneous administration of a cocktail of selective probes (caffeine, mephenytoin, debrisoquin [INN, debrisoquine], chlorzoxazone, and dapsone, respectively), phenotypic indices for metabolism of these drugs were used as measures of individual CYP activity. Sex bioequivalence analysis used the bootstrap method.
  
  
  RESULTS
  There were no sex differences associated with CYP1A2 activity. A significant negative correlation (r = -0.572, P < .01) between enzyme activity and age was observed for CYP2C19, but there were no sex differences. CYP2D6 activity showed no dependence on age or sex. In contrast, CYP2E1 activity showed an age-associated increase (r = 0.393, P < .01), which developed earlier in life in male subjects compared with female subjects. These results were further supported by the sex bioequivalence analysis of CYP phenotypic activity, which revealed that sexes were equivalent with respect to CYP2C19 (90% confidence interval [CI], 0.874-1.04), CYP3A4 (90% CI, 0.95-1.176), and CYP2D6 (90% CI, 0.928-1.09) phenotype and just exceeded the 0.8 to 1.25 limits to be equivalent with respect to CYP2E1 (90% CI, 0.785-1.08) and CYP1A2 (90% CI, 0.736-1.03) phenotype.
  
  
  CONCLUSIONS
  These observations suggest that the presence of selective mechanisms of regulation for individual CYP enzymes can be influenced by age and sex. However, we suggest that sex has a limited ability to explain intersubject variation of activity for these phenotypic measures of CYP enzyme activity.
authors.affiliation: Center for Clinical Pharmacology and Department of Pharmaceutical Sciences, University of Pittsburgh, PA 15219, USA.
authors.forename: Zourab
authors.initials: Z
authors.lastname: Bebia
authors.forename: Shama C
authors.initials: SC
authors.lastname: Buch
authors.forename: John W
authors.initials: JW
authors.lastname: Wilson
authors.forename: Reginald F
authors.initials: RF
authors.lastname: Frye
authors.forename: Marjorie
authors.initials: M
authors.lastname: Romkes
authors.forename: Alfred
authors.initials: A
authors.lastname: Cecchetti
authors.forename: Diego
authors.initials: D
authors.lastname: Chaves-Gnecco
authors.forename: Robert A
authors.initials: RA
authors.lastname: Branch
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000465:Algorithms; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D010641:Phenotype; D012727:Sex Characteristics; D013810:Therapeutic Equivalency
chemical_list: D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System