Table 7.
Clinical significance of transporter genetic polymorphism on the pharmacokinetics of antiviral nucleoside analogs
| Drug | Polymorphism | Subjects | Regulated transporters | Pharmacokinetic impact | Ref |
|---|---|---|---|---|---|
| Tenofovir disoproxil fumarate | ABCC4 (rs3742106) | HIV patients | MRP4 | After adjusting for weight, eGFR, and the concomitant use of ritonavir-boosted protease inhibitors, a 30% increase in the mean tenofovir plasma concentration was observed in patients having the ABCC4 4131 TG or GG genotype. | [92] |
| Tenofovir disoproxil fumarate | ABCC4 (rs1751034) | HIV patients | MRP4 | ABCC4 3463A>G variants had 35% higher TFV-DP intracellular concentrations than wild type (p = 0.04). | [174] |
| Tenofovir disoproxil fumarate | ABCC4 (rs1751034) | HIV patients | MRP4 | ABCC4 3463A>G polymorphism was associated with tenofovir apparent oral clearance (CL/F). Patients carrying ABCC4 3463 AG or GG had a tenofovir CL/F 11% higher than those with genotype AA. | [170] |
| Tenofovir disoproxil fumarate | ABCC4 (rs1751034) ABCC2 (rs717620) |
HIV patients | MRP4, MRP2 | After controlling for race and GFR, ABCC2 –24C>T carriers excreted 19% more tenofovir than wild type (P = 0.04); ABCC4 3463G variant carriers had tenofovir AUC 32% higher than wild type (p = 0.04). | [85] |
| Tenofovir disoproxil fumarate | ABCC2 (rs717620) | HIV patients | MRP2 | ABCC2 –24C>T is associated with decreased eGFR and higher plasma tenofovir concentration (p = 0.018) | [175] |
| Tenofovir disoproxil fumarate | ABCG2 (rs2231142) | HIV patients | BCRP | ABCG2 rs2231142 was associated with tenofovir AUC with rare allele carriers displaying 1.51-fold increase in tenofovir AUC (p < 0.0001). | [176] |
| Tenofovir disoproxil fumarate | ABCB1 (rs3213619) SLC28A1 (rs2242046) |
HIV patients | CNT1, P-gp | The polymorphisms at ABCB1 129T>C (rs3213619) and SLC28A1 1561 G>A (rs2242046) were significantly associated with decreased tenofovir CL/F. Age and creatine clearance are also predictors for tenofovir CL/F. | [93] |
| Tenofovir disoproxil fumarate | SLC28A2 (rs11854484) | HIV patients | CNT2 | SLC28A2 124C>T genotypes were associated with plasma tenofovir exposure (p = 0.05) | [96] |
| Ribavirin | ABCB1 (rs2032582) | HCV patients | P-gp | ABCB1 2677 G > T was statistically associated with ribavirin Ctrough levels after 4 weeks of therapy, while it has not shown any statistically significant association with ribavirin plasma levels or response. | [94] |
| Ribavirin | SLC29A1 (rs760370) | HIV patients with HCV | ENT1 | The polymorphism at the ENT1 gene influences the chance of rapid virological response to pegIFN-ribavirin therapy, modulating intracellular ribavirin exposure within hepatocytes. | [70] |
| Ribavirin | SLC29A1 (rs760370) SLC28A2 (rs11854484) SLC28A3 (rs10868138) |
HCV patients | ENT1, CNT2, CNT3 | SLC28A2 124 TT was related to lower Ctrough levels (TT vs CT/CC, p = 0.048). Patients with SLC28A3 rs10868138 TC (TC vs TT, p = 0.006) and SLC29A1 rs760370 GG (GG vs AG/AA, p = 0.016) genotype had higher ribavirin levels. | [97] |
| Ribavirin | SLC28A2 (rs11854484) | HCV patients | CNT2 | Patients with SLC28A2 124 TT had higher dosage- and body weight-adjusted ribavirin levels than those with genotypes TC or CC (p = 0.02 and p = 0.06 at weeks 4 and 8, respectively). | [31] |
| Efavirenz | ABCB1 (rs1045642) | HIV-infected adults | P-gp | ABCB1 3435C>T was associated with higher efavirenz plasma levels in the standard but not the lower dose group (TC vs CC, p = 0.009). No relationship was found between pharmacogenomics and antiretroviral efficacy. | [95] |
| Lamivudine Zidovudine | ABCC4 (rs3742106) ABCC4 (rs11568695) |
HIV-infected adults | MRP4 | Lamivudine-triphosphate concentrations in PBMCs were elevated by 20% in ABCC4 4131G>T variant carriers (p = 0.004). A trend for elevated zidovudine-triphosphates was observed in MRP4 3724 G>A variant carriers (p = 0.06). | [43] |