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Investigation of the in vivo activity of CYP3A in Brazilian volunteers: comparison of midazolam and omeprazole as drug markers

  • Pharmacokinetics and Disposition
  • Published:
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Abstract

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.

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Acknowledgements

The authors are grateful to Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Fundação de Apoio a Pesquisa e Assistência do HCFMRP-USP (FAEPA) and to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for financial support and for granting research fellowships.

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Authors and Affiliations

  1. Departamento de Análises Clínicas, Toxicológicas and Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil

    Adriana Rocha & Vera L. Lanchote

  2. Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil

    Eduardo B. Coelho & Soraia A. P. Moussa

  3. Departamento de Análises Clínicas, Toxicológicas and Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Avenida do Café s.n. Campus da USP, 14040-903, Ribeirão Preto, SP, Brazil

    Vera L. Lanchote

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  1. Adriana Rocha
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  2. Eduardo B. Coelho
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  3. Soraia A. P. Moussa
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  4. Vera L. Lanchote
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Correspondence to Vera L. Lanchote.

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Rocha, A., Coelho, E.B., Moussa, S.A.P. et al. Investigation of the in vivo activity of CYP3A in Brazilian volunteers: comparison of midazolam and omeprazole as drug markers. Eur J Clin Pharmacol 64, 901–906 (2008). https://doi.org/10.1007/s00228-008-0510-x

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  • DOI: https://doi.org/10.1007/s00228-008-0510-x

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