Effects of ABCB1 (multidrug resistance transporter) gene mutations on disposition and central nervous effects of loperamide in healthy volunteers.

Objective: Mutations in the ABCB1 gene have been associated with decreased expression and net function of P-glycoprotein (P-gp). We investigated the modulation of the central nervous effects of loperamide resulting from ABCB1 genetic variants.

Methods: On two occasions, 20 healthy volunteers received 24 mg loperamide suspension orally and, in a double-blind randomized two-way crossover fashion, 800 mg quinidine or placebo orally 1 h before loperamide. Pupil size was measured for 5 h following loperamide administration, and plasma concentrations of loperamide and quinidine were measured for 6 h. Single nucleotide polymorphisms and haplotypes including G2677T(A) (exon 21) and C3435T (exon 26) were analysed for their relation to plasma concentrations of quinidine and loperamide and to the miotic effects of loperamide.

Results: Loperamide plasma concentrations with quinidine co-administration were about twice as high as those without quinidine. The ABCB1 haplotype G2677/T3435 was associated with the highest loperamide plasma concentrations, which were about 1.5 times higher than in non-carriers of this haplotype. Plasma concentrations of quinidine did not differ among carriers and non-carriers of genetic variants. When quinidine was co-administered with loperamide, pupil size decreased. Without quinidine it changed only minimally. The ABCB1 TT3435 genotype was associated with the most pronounced increase of the miotic effects of loperamide when quinidine was co-administered. This was accompanied by a tendency toward higher plasma loperamide in TT3435 carriers.

Conclusions: Our data support a functional importance of the ABCB1 mutations for plasma concentrations and central nervous actions of the opioid loperamide.