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.
Pharmazentrum frankfurt, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, 60590 Frankfurt, Germany. skarke@em.uni-frankfurt.de
Carsten
C
Skarke
Marwan
M
Jarrar
Helmut
H
Schmidt
Gerold
G
Kauert
Michael
M
Langer
Gerd
G
Geisslinger
Jörn
J
Lötsch
D000284:Administration, Oral; D000483:Alleles; D001483:Base Sequence; D002490:Central Nervous System / Q000187:drug effects*; D002491:Central Nervous System Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D004311:Double-Blind Method; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D019450:Genes, MDR; D014644:Genetic Variation; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008139:Loperamide / Q000493:pharmacokinetics / Q000494:pharmacology*; D015877:Miosis / Q000139:chemically induced; D009154:Mutation; D009294:Narcotics / Q000493:pharmacokinetics / Q000494:pharmacology*; D011680:Pupil / Q000187:drug effects*; D011802:Quinidine / Q000097:blood / Q000494:pharmacology*
D002491:Central Nervous System Agents; D009294:Narcotics; D008139:Loperamide; D011802:Quinidine