Bioequivalence revisited: influence of age and sex on CYP enzymes
| Autor: | Reginald F. Frye, Marjorie Romkes, Zourab Bebia, Shama Buch, Diego Chaves-Gnecco, Alfred A. Cecchetti, John W Wilson, Robert A. Branch |
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| Rok vydání: | 2004 |
| Předmět: |
Adult
Male medicine.medical_specialty CYP2D6 Aging Adolescent Genotype Debrisoquin CYP2C19 Biology Bioequivalence Pharmacology chemistry.chemical_compound Cytochrome P-450 Enzyme System Internal medicine medicine Humans Pharmacology (medical) Mephenytoin Chromatography High Pressure Liquid Aged Aged 80 and over Sex Characteristics Models Statistical CYP3A4 Middle Aged Isoenzymes Endocrinology Phenotype Debrisoquine chemistry Therapeutic Equivalency Female Algorithms medicine.drug Sex characteristics |
| Zdroj: | Clinical pharmacology and therapeutics. 76(6) |
| ISSN: | 0009-9236 |
| Popis: | Background and 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. Conclusion 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. Clinical Pharmacology & Therapeutics (2004) 76, 618–627; doi: 10.1016/j.clpt.2004.08.021 |
| Databáze: | OpenAIRE |
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