Title: MDR1 gene polymorphisms are associated with neuropsychiatric adverse effects of mefloquine
Abstract: Clinical Pharmacology & TherapeuticsVolume 80, Issue 4 p. 367-374 Pharmacogenetics and Genomics MDR1 gene polymorphisms are associated with neuropsychiatric adverse effects of mefloquine Albert L. H. J. Aarnoudse MD, Albert L. H. J. Aarnoudse MD Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, LondonSearch for more papers by this authorRon H. N. van Schaik PhD, Ron H. N. van Schaik PhD Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, LondonSearch for more papers by this authorJeanne Dieleman PhD, Jeanne Dieleman PhD Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, LondonSearch for more papers by this authorMariam Molokhia PhD, Mariam Molokhia PhD Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, LondonSearch for more papers by this authorMelanie M. van Riemsdijk PhD, Melanie M. van Riemsdijk PhD Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, LondonSearch for more papers by this authorRobert J. Ligthelm MD, PhD, Robert J. Ligthelm MD, PhD Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, LondonSearch for more papers by this authorDavid Overbosch MD, PhD, David Overbosch MD, PhD Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, LondonSearch for more papers by this authorIlse P. van der Heiden, Ilse P. van der Heiden Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, LondonSearch for more papers by this authorBruno H. Ch. Stricker PhD, Corresponding Author Bruno H. Ch. Stricker PhD Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, London Bruno H. Ch. Stricker, PhD, Department of Epidemiology & Biostatistics, Erasmus University Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: [email protected]Search for more papers by this author Albert L. H. J. Aarnoudse MD, Albert L. H. J. Aarnoudse MD Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, LondonSearch for more papers by this authorRon H. N. van Schaik PhD, Ron H. N. van Schaik PhD Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, LondonSearch for more papers by this authorJeanne Dieleman PhD, Jeanne Dieleman PhD Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, LondonSearch for more papers by this authorMariam Molokhia PhD, Mariam Molokhia PhD Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, LondonSearch for more papers by this authorMelanie M. van Riemsdijk PhD, Melanie M. van Riemsdijk PhD Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, LondonSearch for more papers by this authorRobert J. Ligthelm MD, PhD, Robert J. Ligthelm MD, PhD Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, LondonSearch for more papers by this authorDavid Overbosch MD, PhD, David Overbosch MD, PhD Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, LondonSearch for more papers by this authorIlse P. van der Heiden, Ilse P. van der Heiden Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, LondonSearch for more papers by this authorBruno H. Ch. Stricker PhD, Corresponding Author Bruno H. Ch. Stricker PhD Departments of Epidemiology and Biostatistics, Clinical Chemistry, and Medical Informatics, Erasmus Medical Center, Institute for Tropical Diseases, Harbour Hospital, Rotterdam Inspectorate of Health Care, The Hague London School of Hygiene and Tropical Medicine, London Bruno H. Ch. Stricker, PhD, Department of Epidemiology & Biostatistics, Erasmus University Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: [email protected]Search for more papers by this author First published: 22 October 2006 https://doi.org/10.1016/j.clpt.2006.07.003Citations: 5Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Abstract 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 References 1van Riemsdijk, M. M., van der Klauw, M. M., Pepplinkhuizen, L. and Stricker, B. H. (1997). Spontaneous reports of psychiatric adverse effects to mefloquine in the Netherlands. Br J Clin Pharmacol 44: 105–106. 2van Riemsdijk, M. M., Ditters, J. M., Sturkenboom, M. C., Tulen, J. H., Ligthelm, R. J. and Overbosch, D., et al. (2002). Neuropsychiatric events during prophylactic use of mefloquine before travelling. Eur J Clin Pharmacol 58: 441–445. 3Barrett, P. J., Emmins, P. D., Clarke, P. D. and Bradley, D. J. (1996). Comparison of adverse events associated with use of mefloquine and combination of chloroquine and proguanil as antimalarial prophylaxis: postal and telephone survey of travellers. BMJ 313: 525–528. 4van Riemsdijk, M. M., Sturkenboom, M. C., Ditters, J. M., Tulen, J. H., Ligthelm, R. J. and Overbosch, D., et al. (2004). Low body mass index is associated with an increased risk of neuropsychiatric adverse events and concentration impairment in women on mefloquine. Br J Clin Pharmacol 57: 506–512. 5Schwartz, E., Potasman, I., Rotenberg, M., Almog, S. and Sadetzki, S. (2001). Serious adverse events of mefloquine in relation to blood level and gender. Am J Trop Med Hyg 65: 189–192. 6Schlagenhauf, P., Steffen, R., Lobel, H., Johnson, R., Letz, R. and Tschopp, A., et al. (1996). Mefloquine tolerability during chemoprophylaxis: focus on adverse event assessments, stereochemistry and compliance. Trop Med Int Health 1: 485–494. 7Hoffmeyer, S., Burk, O., von Richter, O., Arnold, H. P., Brockmoller, J. and Johne, A., et al. (2000). Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A 97: 3473–3478. 8Marzolini, C., Paus, E., Buclin, T. and Kim, R. B. (2004). Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 75: 13–33. 9Riffkin, C. D., Chung, R., Wall, D. M., Zalcberg, J. R., Cowman, A. F. and Foley, M., et al. (1996). Modulation of the function of human MDR1 P-glycoprotein by the antimalarial drug mefloquine. Biochem Pharmacol 52: 1545–1552. 10Morita, Y., Sakaeda, T., Horinouchi, M., Nakamura, T., Kuroda, K. and Miki, I., et al. (2003). MDR1 genotype-related duodenal absorption rate of digoxin in healthy Japanese subjects. Pharm Res 20: 552–556. 11Kurata, Y., Ieiri, I., Kimura, M., Morita, T., Irie, S. and Urae, A., et al. (2002). Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clin Pharmacol Ther 72: 209–219. 12Hesselink, D. A., van Schaik, R. H., van der Heiden, I. P., van der Werf, M., Gregoor, P. J. and Lindemans, J., et al. (2003). Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 74: 245–254. 13Wald, F. D. M. and Mellenbergh, G. J. (1990). De verkorte versie van de Nederlandse vertaling van de Profile of Mood States (POMS). Ned Tijdschr Psychol 45: 86–90. 14Baker, E. L., Letz, R. and Fidler, A. (1985). A computer-administered neurobehavioral evaluation system for occupational and environmental epidemiology: Rationale, methodology, and pilot study results. J Occup Med 27: 206–212. 15Letz, R. (1991). Use of computerized test batteries for quantifying neurobehavioral outcomes. Environ Health Perspect 90: 195–198. 16Green, M. D., Bergqvist, Y., Mount, D. L., Corbett, S. and D'Souza, M. J. (1999). Improved validated assay for the determination of mefloquine and its carboxy metabolite in plasma, serum and whole blood using solid-phase extraction and high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 727: 159–165. 17Stephens, M., Smith, N. J. and Donnelly, P. (2001). A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68: 978–989. 18Stephens, M. and Donnelly, P. (2003). A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73: 1162–1169. 19 fastPHASE: software for haplotype reconstruction, and estimating missing genotypes from population data. Available from URL: http://www.stat.washington.edu/stephens/software.html. Accessed Sept 11, 2006. 20Barrett, J. C., Fry, B., Maller, J. and Daly, M. J. (2005). Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21: 263–265. 21 Haploview. Available from: URL: http://www.broad.mit.edu/mpghaploview. Accessed Sept 12, 2006. 22Gerloff, T., Schaefer, M., Johne, A., Oselin, K., Meisel, C. and Cascorbi, I., et al. (2002). MDR1 genotypes do not influence the absorption of a single oral dose of 1 mg digoxin in healthy white males. Br J Clin Pharmacol 54: 610–616. 23Kroetz, D. L., Pauli-Magnus, C., Hodges, L. M., Huang, C. C., Kawamoto, M. and Johns, S. J., et al. (2003). Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics 13: 481–494. 24Baudry, S., Pham, Y. T., Baune, B., Vidrequin, S., Crevoisier, C. and Gimenez, F., et al. (1997). Stereoselective passage of mefloquine through the blood-brain barrier in the rat. J Pharm Pharmacol 49: 1086–1090. 25Babaoglu, M. O., Bayar, B., Aynacioglu, A. S., Kerb, R., Abali, H. and Celik, I., et al. (2005). Association of the ABCB1 3435C>T polymorphism with antiemetic efficacy of 5-hydroxytryptamine type 3 antagonists. Clin Pharmacol Ther 78: 619–626. 26Skarke, C., Jarrar, M., Schmidt, H., Kauert, G., Langer, M. and Geisslinger, G., et al. (2003). Effects of ABCB1 (multidrug resistance transporter) gene mutations on disposition and central nervous effects of loperamide in healthy volunteers. Pharmacogenetics 13: 651–660. 27van Riemsdijk, M. M., Sturkenboom, M. C., Ditters, J. M., Ligthelm, R. J., Overbosch, D. and Stricker, B. H. (2002). Atovaquone plus chloroguanide versus mefloquine for malaria prophylaxis: a focus on neuropsychiatric adverse events. Clin Pharmacol Ther 72: 294–301. 28Schuetz, E. G., Furuya, K. N. and Schuetz, J. D. (1995). Interindividual variation in expression of P-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther 275: 1011–1018. 29Saitoh, A., Singh, K. K., Powell, C. A., Fenton, T., Fletcher, C. V. and Brundage, R., et al. (2005). An MDR1–3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children. AIDS 19: 371–380. 30Johne, A., Kopke, K., Gerloff, T., Mai, I., Rietbrock, S. and Meisel, C., et al. (2002). Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin Pharmacol Ther 72: 584–594. 31Verstuyft, C., Schwab, M., Schaeffeler, E., Kerb, R., Brinkmann, U. and Jaillon, P., et al. (2003). Digoxin pharmacokinetics and MDR1 genetic polymorphisms. Eur J Clin Pharmacol 58: 809–812. 32Morita, N., Yasumori, T. and Nakayama, K. (2003). Human MDR1 polymorphism: G2677T/A and C3435T have no effect on MDR1 transport activities. Biochem Pharmacol 65: 1843–1852. 33Siegmund, W., Ludwig, K., Giessmann, T., Dazert, P., Schroeder, E. and Sperker, B., et al. (2002). The effects of the human MDR1 genotype on the expression of duodenal P-glycoprotein and disposition of the probe drug talinolol. Clin Pharmacol Ther 72: 572–583. 34Pauli-Magnus, C., Feiner, J., Brett, C., Lin, E. and Kroetz, D. L. (2003). No effect of MDR1 C3435T variant on loperamide disposition and central nervous system effects. Clin Pharmacol Ther 74: 487–498. 35Chowbay, B., Li, H., David, M., Bun Cheung, Y. and Lee, E. J. (2005). Meta-analysis of the influence of MDR1 C3435T polymorphism on digoxin pharmacokinetics and MDR1 gene expression. Br J Clin Pharmacol 60: 159–171. 36Wang, D., Johnson, A. D., Papp, A. C., Kroetz, D. L. and Sadee, W. (2005). Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics 15: 693–704. Citing Literature Volume80, Issue4October 2006Pages 367-374 ReferencesRelatedInformation
Publication Year: 2006
Publication Date: 2006-10-01
Language: en
Type: article
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 75
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