No effect of MDR1 C3435T variant on loperamide disposition and central nervous system effects.
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.


CONCLUSIONS
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.
Department of Biopharmaceutical Sciences, University of California, San Francisco, CA 94143-0446, USA.
Christiane
C
Pauli-Magnus
John
J
Feiner
Claire
C
Brett
Emil
E
Lin
Deanna L
DL
Kroetz
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000328:Adult; D000930:Antidiarrheals / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001711:Biotransformation; D002245:Carbon Dioxide / Q000494:pharmacology; D002490:Central Nervous System / Q000187:drug effects*; D003864:Depression, Chemical; D005260:Female; D019450:Genes, MDR / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007408:Intestinal Absorption / Q000235:genetics; D008139:Loperamide / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D015656:Respiratory Mechanics / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000930:Antidiarrheals; D002245:Carbon Dioxide; D008139:Loperamide