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MDR1 gene polymorphisms are associated with neuropsychiatric adverse effects of mefloquine
Author(s) -
Aarnoudse Albert L. H. J.,
Schaik Ron H. N.,
Dieleman Jeanne,
Molokhia Mariam,
Riemsdijk Melanie M.,
Ligthelm Robert J.,
Overbosch David,
Heiden Ilse P.,
Stricker Bruno H. Ch.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2006.07.003
Subject(s) - haplotype , mefloquine , adverse effect , medicine , odds ratio , genotype , single nucleotide polymorphism , allele , polymorphism (computer science) , confidence interval , pharmacology , genetics , biology , malaria , immunology , gene , chloroquine
Background Mefloquine, a drug used for treatment and prophylaxis of malaria, is known for its neuropsychiatric adverse effects. We hypothesized that neuropsychiatric adverse effects of mefloquine are associated with polymorphisms in the MDR1 / ABCB1 gene that encodes for the efflux pump P‐glycoprotein. Methods The association between MDR1 C1236T, G2677T, and C3435T single‐nucleotide polymorphisms and the occurrence of neuropsychiatric adverse effects was examined in a prospective cohort study of 89 healthy white travelers taking mefloquine. Results Of the subjects, 27 (28%) reported neuropsychiatric adverse effects, women significantly more frequently than men. Allele frequencies of the C1236T, G2677T, and C3435T polymorphisms were similar to those found in other white populations, and there was no significant association between any of the individual polymorphisms and neuropsychiatric adverse effects. However, women with the 1236TT, 2677TT, and 3435TT genotypes had a higher risk of neuropsychiatric adverse effects than the reference groups of women with heterozygous and homozygous CC or GG genotypes, with odds ratios of 6.3 (95% confidence interval [CI], 1.1–36.9), 10.5 (95% CI, 1.1–100.6), and 5.4 (95% CI, 1.1–30.0), respectively. The association for women homozygous for the 1236–2677–3435 TTT haplotype was even stronger ( P = .004) than the effect of any of the individual polymorphisms. No associations with mefloquine blood levels were observed. Conclusion In this study the MDR1 1236TT, 2677TT, and 3435TT genotypes, along with the 1236–2677–3435 TTT haplotype, were associated with neuropsychiatric adverse effects of mefloquine in women. MDR1 polymorphisms may play an important role in predicting the occurrence of neuropsychiatric adverse effects of mefloquine, particularly in female travelers. Clinical Pharmacology & Therapeutics (2006) 80 , 367–374; doi: 10.1016/j.clpt.2006.07.003