Assessment of inter-racial variability in CYP3A4 activity and inducibility among healthy adult males of Caucasian and South Asian ancestries
Tóm tắt
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. 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. 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. 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.
Tài liệu tham khảo
Guengerich FP (1995) Human cytochrome P450 enzymes. In: de Montellano PRO (ed) Cytochrome P450: structure, mechanism, and biochemistry. Springer US, Boston, MA, pp 473–535
Wilkinson GR (2005) Drug metabolism and variability among patients in drug response. N Engl J Med 352(21):2211–2221
Perera V, Gross AS, McLachlan AJ (2012) Influence of environmental and genetic factors on CYP1A2 activity in individuals of South Asian and European ancestry. Clin Pharmacol Ther 92:511–519
McGraw J, Waller D (2012) Cytochrome P450 variations in different ethnic populations. Expert Opin Drug Metab Toxicol 8:371–382
Thorn CF, Aklillu E, Klein TE, Altman RB (2012) PharmGKB summary: very important pharmacogene information for CYP1A2. Pharmacogenet Genomics 22:73–77
Zanger UM, Schwab M (2013) Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 138:103–141
Wilkinson GR (1996) Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans. J Pharmacokinet Biopharm 24:475–490
Westlind A, Lofberg L, Tindberg N, Andersson TB, Ingelman-Sundberg M (1999) Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5′-upstream regulatory region. Biochem Biophys Res Commun 259:201–205
Snyder BD, Rowland A, Polasek TM, Miners JO, Doogue MP (2014) Evaluation of felodipine as a potential perpetrator of pharmacokinetic drug-drug interactions. Eur J Clin Pharmacol 70:1115–1122
Rowland A, van Dyk M, Warncken D, Mangoni A, Sorich M, Rowland A (2017) Evaluation of modafinil as a perpetrator of metabolic drug-drug interactions. Br J Clin Pharmacol 84:501–509
Yamaori S, Yamazaki H, Iwano S, Kiyotani K, Matsumura K, Saito T, Parkinson A, Nakagawa K, Kamataki T (2005) Ethnic differences between Japanese and Caucasians in the expression levels of mRNAs for CYP3A4, CYP3A5, and CYP3A7. Xenobiotica 35:69–83
He P, Court MH, Greenblatt DJ, Von Moltke LL (2005) Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin Pharmacol Ther 77:373–387
Floyd MD, Gervasini G, Masica AL, Mayo G, George ALJ, Bhat K et al (2003) Genotype–phenotype associations for common CYP3A4 and CYP3A5 variants in the basal and induced metabolism of midazolam in European- and African-American men and women. Pharmacogenet Genomics 13:595–606
Roach M, De Silvio M, Rebbick T, Grignon D, Rotman M, Wolkov H et al (2007) Racial differences in CYP3A4 genotype and survival among men treated on radiation therapy oncology group (RTOG) 9202: a phase III randomized trial. Int J Rad Oncol Biol Phys 69:79–87
Lakhman SS, Ma Q, Morse GD (2009) Pharmacogenomics of CYP3A: considerations for HIV treatment. Pharmacogenomics 10:1323–1339
Xie HG, Wood AJ, Kim RB, Stein CM, Wilkinson GR (2004) Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics 5:243–272
Mizutani T (2003) PM frequencies of major CYPs in Asians and Caucasians. Drug Metab Rev 35:99–106
Shih P-S, Huang J-D (2002) Pharmacokinetics of midazolam and 1′-hydroxymidazolam in Chinese with different CYP3A5 genotypes. Drug Metab Dispos 30:1491–1496
Mirghani RA, Sayi J, Aklillu E, Allqvist A, Jande M, Wennerholm A, Eriksen J, Herben VMM, Jones BC, Gustafsson LL, Bertilsson L (2006) CYP3A5 genotype has significant effect on quinine 3-hydroxylation in Tanzanians, who have lower total CYP3A activity than a Swedish population. Pharmacogenet Genomics 16:637–645
Ferraresso M, Turolo S, Belingheri M, Tirelli AS, Cortinovis I, Milani S, Edefonti A, Ghio L (2015) Relationship between mRNA expression levels of CYP3A4, CYP3A5 and SXR in peripheral mononuclear blood cells and aging in young kidney transplant recipients under tacrolimus treatment. Pharmacogenomics 16:483–491
Gashaw I, Kirchheiner J, Goldammer M, Bauer S, Seidemann J, Zoller K, Mrozikiewicz PM, Roots I, Brockmöller J (2003) Cytochrome p450 3A4 messenger ribonucleic acid induction by rifampin in human peripheral blood mononuclear cells. Clin Pharmacol Ther 74:448–457
Haas CE, Brazeau D, Cloen D, Booker BM, Frerichs V, Zaranek C, Frye RF, Kufel T (2005) Cytochrome P450 mRNA expression in peripheral blood lymphocytes as a predictor of enzyme induction. Eur J Clin Pharmacol 61:583–593
Rowland A, Van Dyk M, Mangoni A, Miners J, McKinnon R, Wiese M et al (2017) Kinase inhibitor pharmacokinetics: comprehensive summary and roadmap for addressing variability in exposure. Exp Opin Drug Metab Toxicol 13:31–49
Flexner C (1998) HIV-protease inhibitors. N Engl J Med 338:1281–1293
Jamei M, Dickinson GL, Rostami-Hodjegan A (2009) A framework for assessing inter-individual variability in pharmacokinetics using virtual human populations and integrating general knowledge of physical chemistry, biology, anatomy, physiology and genetics: a tale of ‘bottom-up’ vs ‘top-down’ recognition of covariates. Drug Metab Pharmacokinet 24:53–75
van Dyk M, Rowland A (2017) PBPK modeling as an approach to evaluate the effect of covariates and drug-drug interactions on variability in EGFR kinase inhibitor exposure. Trans Cancer Res In Press