Investigation of the in vivo activity of CYP3A in Brazilian volunteers: comparison of midazolam and omeprazole as drug markers.
OBJECTIVE
This study compares midazolam with omeprazole as marker drugs for the evaluation of CYP3A activity in nine healthy self-reported white Brazilian volunteers.


METHODS
Omeprazole was also used to evaluate the CYP2C19 phenotype. The volunteers received p.o. 20 mg omeprazole, and blood samples were collected 3.5 h after drug administration. After a washout period of 10 days, the volunteers received p.o. 15 mg midazolam maleate, and serial blood samples were collected up to 6 h after administration of the drug. CYP2C19 was genotyped for the allelic variants CYP2C19*1, CYP2C19*2, CYP2C19*3, and CYP2C19*17. Analysis of omeprazole, hydroxyomeprazole, omeprazole sulfone, and midazolam in plasma was carried out by LC-MS/MS.


RESULTS
The volunteers genotyped as CYP2C19*1*17, CYP2C19*17*17, CYP2C19*1*1 (n = 8), or CYP2C19*17*2 (n = 1) presented a median hydroxylation index (omeprazole/hydroxyomeprazole) of 1.35, indicating that all of them were extensive metabolizers of CYP2C19. The volunteers (n = 9) presented a 0.12 log of the omeprazole/sulfone ratio and a median oral clearance of midazolam of 17.89 ml min(-1) kg(-1), suggesting normal CYP3A activity.


CONCLUSIONS
Orthogonal regression analysis between midazolam clearance and log of the plasma concentrations of the omeprazole/omeprazole sulfone ratio (R = -0.7544, P < 0.05) suggests that both midazolam and omeprazole can be used as markers of CYP3A activity in the population investigated.
Rocha
Adriana
A
Departamento de Análises Clínicas, Toxicológicas and Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
Coelho
Eduardo B
EB
Moussa
Soraia A P
SA
Lanchote
Vera L
VL
D000328:Adult; D000897:Anti-Ulcer Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D015415:Biomarkers / Q000097:blood; D001938:Brazil; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D009853:Omeprazole / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D010641:Phenotype; D055815:Young Adult
D000897:Anti-Ulcer Agents; D015415:Biomarkers; D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A; D009853:Omeprazole; D008874:Midazolam