Heritability of digoxin pharmacokinetics

Abstract

Background/Aims The clinical significance of genetic variability in membrane transporters is still unclear. In this study, we compared digoxin pharmacokinetics in monozygotic (MZ) and dizygotic (DZ) twin pairs to test the hypothesis that genetic differences contribute to interindividual variability in digoxin disposition. Digoxin is minimally metabolized in humans and its bioavailability is highly dependent on drug transporters. Methods Each twin pair (10 MZ and 6 DZ) was administered a 1 mg oral dose of digoxin and plasma and urine were collected over 3 days. Pharmacokinetic parameters were estimated using standard methods. A preliminary estimate of heritability was calculated using variability between and within the MZ twin pairs (rGC= (Vbetween−Vwithin)/Vbetween). Results Preliminary estimates indicate that 36% of the variability in oral clearance (CL/F) can be attributed to genetics (rGC= 0.359). In contrast, genetics accounts for only a minor component of the variability in CLR (rGC= 0.19). Data from DZ twin pairs will be used to estimate the true heritability index. Conclusions These studies suggest that digoxin oral clearance is influenced by both environmental and genetic differences among individuals. Future studies will determine the contribution of genetic polymorphisms in membrane transporters involved in digoxin bioavailability on interindividual variability in digoxin pharmacokinetics. Clinical Pharmacology & Therapeutics (2005) 77, P21–P21; doi: 10.1016/j.clpt.2004.11.083