In vivo comparison of putative probes of CYP3A4/5 activity: erythromycin, dextromethorphan, and verapamil
| Autor: | Irving W. Wainer, Janice B. Schwartz, Mary Ellen Krecic‐Shepard, J. Christopher Gorski, Crissy R. Barnas, Jill Slimko |
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| Rok vydání: | 1999 |
| Předmět: |
Adult
Male Metabolite Administration Oral Pharmacology Dextromethorphan Mixed Function Oxygenases chemistry.chemical_compound Route of administration Pharmacokinetics Cytochrome P-450 Enzyme System Oral administration Reference Values medicine Cytochrome P-450 CYP3A Humans Pharmacology (medical) Infusions Intravenous Aged Aged 80 and over Chemistry Norverapamil Middle Aged Erythromycin breath test Anti-Bacterial Agents Erythromycin Antitussive Agents Breath Tests Verapamil Area Under Curve Linear Models Female Anti-Arrhythmia Agents medicine.drug |
| Zdroj: | Clinical pharmacology and therapeutics. 66(1) |
| ISSN: | 0009-9236 |
| Popis: | Objectives Multiple in vivo CYP3A4/5 probes have been proposed. We compared verapamil clearance measures (CYP3A4/5 substrate) to the erythromycin breath test (ERBT) and the cumulative urinary dextromethorphan/3-methoxymorphinan test. Methods Clearance of intravenous and oral racemic verapamil and the area under the plasma concentration versus time curve (AUC) ratio of norverapamil (N-demethylated metabolite) to verapamil after oral verapamil dosing, the ERBT, and the dextromethorphan urinary metabolite ratios were measured in 84 healthy nonsmoking subjects (42 men and 42 women; age, 47 ± 23 (mean ± SD) years; weight, 69 ± 11 kg). Relationships between putative CYP3A4/5 probes were assessed by linear regression. Results The strongest correlation was between intravenous and oral verapamil clearance (r2 = 0.26; P = .0001). Relationships between cumulative urinary dextromethorphan/3-methoxymorphinan and (1) intravenous verapamil clearance (r2 = 0.073; P = .024), (2) oral verapamil clearance (r2 = 0.144; P = .001), and (3) plasma AUCnorverapamil/AUCverapamil after oral verapamil (r2 = 0.10; P = .01) were also detected. The ERBT and intravenous verapamil clearance were weakly related (r2 = 0.04; P = .067). No relationship was detected between ERBT and dextromethorphan/3-methoxymorphinan ratios (r2 = 0.00006; P = .945), oral verapamil clearance (r2 = 0.00006; P = .94), or plasma AUCnorverapamil/AUCverapamil after oral verapamil (r2 = 0.0002; P = .9). Conclusions Intravenous and oral verapamil clearance values were significantly correlated, and cumulative dextromethorphan/3-methoxymorphinan urinary ratios correlated with both plasma AUCnorverapamil/AUCverapamil after oral verapamil dosing and with oral and intravenous verapamil clearance. The ERBT correlated only weakly with intravenous verapamil clearance. Results with verapamil are comparable to results with other intravenous and oral CYP3A4/5 probes. Lack of correlation between putative CYP3A4/5 probe results may be attributable to the route of administration; probe characteristics; and intersubject, intrasubject, between-day, and testing measurement variability. Clinical Pharmacology & Therapeutics (1999) 66, 40–50 |
| Databáze: | OpenAIRE |
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