Journal
PHARMACOGENOMICS
Volume 13, Issue 1, Pages 113-121Publisher
FUTURE MEDICINE LTD
DOI: 10.2217/PGS.11.132
Keywords
CYP2B6; CYP450; Malawi; nevirapine; nuclear receptor; P-glycoprotein; pharmacokinetics
Categories
Funding
- Pharmacogenetics for Every Nation Initiative
- Pharmacogenetics Research Network [NIH U01 GM63340]
- UNC Translational and Clinical Sciences Institute [ULIRR025747]
- NIH [GM60346]
- Cancer Center Support [NIH P30 CA21765]
- American Lebanese Syrian Associated Charities (ALSAC)
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Aim: Genetic polymorphisms have the potential to influence drug metabolism and vary among ethnic groups. This study evaluated the correlation of genetic polymorphisms with nevirapine pharmacokinetics exposure in Malawians. Materials & methods: CYP450 286, 2D6, 3A4 and 3A5, ABCB1 and constitutive androstane receptor and pregnane X receptor, were analyzed for polymorphisms in 26 subjects. Results: Allele frequencies (variant) were: CYP286 514G>T (0.31) CYP2D6*4 (0.02); CYP2D6*17 (0.35); CYP3A4*18 (0.77); CYP3A5*3 (0.25); ABCB1 2677G>T (0.0), ABCB1 3435C>T (0.21), NR1I3 13711152T>C (0.02), NR1I2 44477T>C (0.10), NR1I2 63396C>T (0.33), NR1I2 6-bp indel (del: 0.17). CYP286 516G>T (non-wild-type/wild-type) correlated with nevirapine pharmacokinetic parameters; geometric mean ratios (95% CI): 1.75 (1.27-2.40) for area under the concentration time curve (AUC)(0-12 h), 1.58 (1.03-2.42) for C-0, and 0.53 (0.31-0.91) for clearance. In a multivariable model, nevirapine AUC increased by 1.5% per year of age (p < 0.0001), CYP286 516 T allele increased AUC by 92% (p < 0.0001), and CYP3A5*3 decreased AUC by 31% (p = 0.0027). Conclusion: Allele frequencies were similar to other sub-Saharan African populations. The T allele for CYP286 516 was significantly associated with nevirapine exposure.
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