2. University of Maryland School of Medicine, Baltimore, Maryland.
3. Annapolis Nephrology Associates, Annapolis, Maryland.
Background: Type 2 diabetes mellitus (T2DM) is highly prevalent in the Latino population. Many antidiabetic drugs such as sulfonylureas, dipeptidylpeptidase-4 inhibitors and pioglitizone, are metabolized in the liver by polymorphic cytochrome-P450 (CYP) enzymes including CYP2B6, CYP3A5, and CYP2C9. The prevalence of CYP allelic variants is largely unknown in Latino patients with T2DM. The objective of this study was to evaluate liver function and drug metabolism in a medically underserved population of Latino patients with T2DM.
Methods: This pilot study included 14 Latinos and 12 age-matched non-Hispanic controls. Genetic variants of CYP2B6, CYP3A5 and CYP2C9 were identified by polymerase chain reaction using TaqMan allelic discrimination. Hepatic CYP3A phenotype was measured by the erythromycin breath test (ERMBT). Kidney function was estimated by CLcr and GFR was measured by iothalamate clearance. The Shapiro-Wilk test was used to evaluate normality distribution, and between-group comparisons were made using either t-test or Mann-Whitney U.
Results: Latino subjects had poorly controlled T2DM as evidenced by hemoglobin A1C values > 7.0%. Hepatic CYP3A phenotype, measured by ERMBT, was 22% lower than controls (p=0.047). The CYP3A5*3 splice variant was present in all subjects. In CYP3A5*1 carriers, EBT values were slightly higher than those homozygous for the *3 allele (2.32 ± 0.04% vs. 1.96 ± 0.47%, p=0.2). Seven out of 11 subjects (64%) were homozygous for the CYP2B6*6 allele, and 10 out of 11 (91%) were carriers of the 2B6*6 allele. There were no subjects possessing the CYP3A5*6 or CYP2C9*3 alleles. Kidney function testing showed a mean urinary albumin-to-creatinine ratio (ACR) of 24 ± 47 mg/g and measured GFR of 141 ± 24 mL/min. Creatinine clearance was significantly higher in Latino subjects compared to controls (145 ± 33 mL/min vs. 102 ± 21 mL/min, p<0.001).
Conclusion: This evaluation of drug metabolism in Latino patients with diabetes identified polymorphic variants of CYP2B6 and CYP3A5 associated with reduced CYP enzyme activity in the presence of glomerular hyperfiltration. Further studies are needed to confirm these findings and to understand the implications in drug selection for Latino patients with T2DM.
Keywords: Kidney function, Glomerular filtration rate (GFR), Cytochrome P-450 (CYP), pharmacogenomics, Hispanic Americans, type 2 diabetes