Background: The MDR1 gene encodes the efflux transporter P-glycoprotein, which is highly expressed in the small intestine and in the blood-brain barrier. A major function of P-glycoprotein is to limit the absorption and central nervous system exposure of numerous xenobiotics. A genetic polymorphism in the MDR1 gene (C3435T) has been associated with changes in the intestinal expression level and function of P-glycoprotein. The aim of this study was to investigate the effect of this polymorphism on disposition and brain entry of the P-glycoprotein substrate loperamide.
Methods: Healthy white volunteers were genotyped for the MDR1 C3435T polymorphism, and a 16-mg oral dose of loperamide was administered to 8 subjects with the 3435TT genotype and 8 subjects with the 3435CC genotype. Plasma levels of loperamide were determined by liquid chromatography-tandem mass spectrometry. Loperamide-induced respiratory depression was detected as the ventilatory response to carbon dioxide and was used as a measure of central nervous system side effects.
Results: We found no significant difference in loperamide pharmacokinetics between individuals homozygous for the C and the T alleles in position 3435 of MDR1, as follows: peak plasma drug concentration, 3164 +/- 1053 pg/mL and 3021 +/- 984 pg/mL; area under the concentration-time curve from 0 to 8 hours, 14414 +/- 4756 pg. h/mL and 14923 +/- 6466 pg. h/mL; and time to peak plasma drug concentration, 3.9 +/- 1.4 hours and 3.9 +/- 2.6 hours for the MDR1 3435CC and 3435TT genotypes, respectively (P >.05, for all parameters). Hypercapnic ventilatory response changed only minimally after ingestion of loperamide (the coefficient of variation during the 0- to 8-hour period was 21% +/- 14% for the sample population), and there was no MDR1 3435 genotype-related effect on respiratory response. Carriers of the 2 major MDR1 haplotypes, MDR1*1 and MDR1*13, did not differ in their response to loperamide.
Conclusion: There was no association between the MDR1 C3435T variation and plasma levels or central nervous system effects of the P-glycoprotein substrate loperamide in a white study population. The MDR1 haplotype structure was quite variable and supports the use of haplotypes instead of single nucleotide polymorphisms in determining clinical consequences of genetic variation.