¹Department of Biopharmaceutical Sciences, Department of Anesthesiology, Liver Center, and Program in Human Genetics, University of California, San Francisco, Calif, USA

Correspondence: Deanna L. Kroetz, PhD, Department of Biopharmaceutical Sciences, University of California, San Francisco, 513 Parnassus Ave, San Francisco, CA 94143-0446, USA. E-mail: deanna@itsa.ucsf.edu

^*This work was supported by grants from the National Institutes of Health (GM61390) and the Robert Black Charitable Foundation. Dr Pauli-Magnus was supported by a fellowship from the Robert Bosch Foundation.

Received 4 February 2003; Accepted 10 July 2003.

Abstract

Background: The MDR1 gene encodes the efflux transporter P-glycoprotein, which is highlyexpressed 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 a6-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, 14,414 4,756 pg h/mL and 14,923 6,466 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.