Effects of different genotypes on the pharmacokinetics of probe substrates may support their use as phenotyping agents for the activity of the respective enzyme or transporter. Digoxin is recommended as a probe substrate to assess the activity of the transporter P-glycoprotein (P-gp) in humans. Current studies on the individual effects of three commonly investigated single nucleotide polymorphisms (SNPs) of the ABCB1 gene encoding P-gp (C1236T, G2677T/A, and C3435T) on digoxin pharmacokinetics are inconclusive. Since SNPs are in incomplete linkage disequilibrium, considering combinations of these SNPs might be necessary to assess the role of polymorphisms in digoxin pharmacokinetics accurately. In this study, the relationship between SNP combinations and digoxin pharmacokinetics was explored via a population pharmacokinetic approach in 40 volunteers who received oral doses of 0.5 mg digoxin. Concerning the SNPs 1236/2677/3435, the following combinations were evaluated: CGC, CGT, and TTT. Carriers of CGC/CGT and TTT/TTT had 35% higher apparent bioavailability compared to the reference group CGC/CGC, while no difference was seen in CGC/TTT carriers. No significant effect on renal clearance was observed. The population pharmacokinetic model supports the use of oral digoxin as a phenotyping substrate of intestinal P-gp, but not to assess renal P-gp activity.
Trial registration: ClinicalTrials.gov NCT02515526 NCT02743260.