Assessment of inter-racial variability in CYP3A4 activity and inducibility among healthy adult males of Caucasian and South Asian ancestries.
Eur J Clin Pharmacol
; 74(7): 913-920, 2018 Jul.
Article
em En
| MEDLINE
| ID: mdl-29572563
ABSTRACT
PURPOSE:
Cytochrome P450 (CYP) 3A4 is responsible for the metabolism of more than 30% of clinically used drugs. Inherent between subject variability in clearance of CYP3A4 substrates is substantial; by way of example, midazolam clearance varies by > 10-fold between individuals before considering the impact of extrinsic factors. Relatively little is known about inter-racial variability in the activity of this enzyme.METHODS:
This study assessed inter-racial variability in midazolam exposure in a cohort (n = 30) of CYP3A genotyped, age-matched healthy males of Caucasian and South Asian ancestries. Midazolam exposure was assessed at baseline, following 7 days of rifampicin and following 3 days of clarithromycin.RESULTS:
The geometric mean baseline midazolam area under the plasma concentration curve (AUC0-6) in Caucasians (1057 µg/L/min) was 27% greater than South Asians (768 µg/L/min). Similarly, the post-induction midazolam AUC0-6 in Caucasians (308 µg/L/min) was 50% greater than South Asians (154 µg/L/min), while the post-inhibition midazolam AUC0-6 in Caucasians (1834 µg/L/min) was 41% greater than South Asians (1079 µg/L/min). The difference in baseline AUC0-6 between Caucasians and South Asians was statistically significant (p ≤ 0.05), and a trend toward significance (p = 0.067) was observed for the post-induction AUC0-6 ratio, in both unadjusted and genotype adjusted analyses.CONCLUSIONS:
Significantly higher midazolam clearance was observed in healthy age-matched males of South Asian compared to Caucasian ancestry that was not explained by differences in the frequency of CYP3A genotypes.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Midazolam
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Povo Asiático
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População Branca
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Citocromo P-450 CYP3A
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Humans
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Male
Idioma:
En
Revista:
Eur J Clin Pharmacol
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Austrália