524a The Effect of ABCB1 (MDR1) Polymorphism on the Plasma and Intracellular Pharmacokinetics of Indinavir and Glucose Handling in Healthy Volunteers. B Maher, PG Hoggard*, B Chandler, ER Meaden, A Owen, DJ Back, SH Khoo, M Pirmohamed Univ of Liverpool, Liverpool, UK
Background: Use of Protease Inhibitors (PIs) is associated with dyslipidaemia and insulin resistance; these are observed even with short-term use of PIs. Since transport by drug efflux pumps such as P-glycoprotein (P-gp) influences the disposition of PIs, we have investigated indinavir (IDV) pharmacokinetics and glucose handling in the absence of HIV infection and immune dysregulation, and related this to the ABCB1 (MDR1) functional polymorphism C3435T.
Methods: RFLP analysis was used to distinguish C and T alleles at position 3435 in 100 healthy volunteers. Twelve subjects, 4 each with the CC, CT, TT genotype were entered into the study. Plasma and intracellular pharmacokinetics of IDV were determined over 24h. Following an overnight fast, volunteers were given a single dose of IDV (1200mg); blood was then sampled at 0, 1, 2, 4, 8, 12 and 24h prior to IDV analysis by LC/MS/MS. Volunteers were given a meal at 2h. Plasma glucose and insulin were also analysed throughout the dosing interval. P-gp expression on lymphocytes was examined by flow cytometry. The homeostatic model of insulin resistance (HOMA-IR) was calculated (fasting insulin [mIU/L] x fasting glucose [mmol/L]/22.5).
Results: There was no significant difference in total plasma and intracellular exposure (AUC0-24h) between the genotypes. However there was a significantly higher IDV 1h plasma concentration in CC individuals than TT (TT 17.3 ± 3.4, CT 23.6 ± 2.9, CC 26.1 ± 1.2µM; ANOVA followed by t-test, p=0.028). The 1h plasma concentration showed a significant relationship with the change from baseline in HOMA-IR at 1h (r2 = 0.30; p = 0.04, simple linear regression).
Conclusions: The effect on IDV plasma concentration at 1h suggests that C3435T genotype is a marker for intestinal transport/metabolism which impacts on the initial systemic availability of IDV. It is now important to assess haplotypes at the MDR1 locus in linkage with C3435T. We have confirmed previous observations that a single dose of IDV affects glucose disposal. Moreover, despite small numbers of subjects in this study plasma levels of IDV at 1h were significantly associated with the magnitude of effect on HOMA-IR. We conclude that MDR-1 genotypes may not only influence therapeutic success but the development of drug induced toxicity.
