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A novel polymorphis...
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Mukonzo, Jackson K
(author)
A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans.
- Article/chapterEnglish2009
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LIBRIS-ID:oai:gup.ub.gu.se/120176
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https://gup.ub.gu.se/publication/120176URI
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https://doi.org/10.1111/j.1365-2125.2009.03516.xDOI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:119596512URI
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-127425URI
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AIMS: Efavirenz exhibits pharmacokinetic variability causing varied clinical response. The aim was to develop an integrated population pharmacokinetic/pharmacogenetic model and investigate the impact of genetic variations, sex, demographic and biochemical variables on single-dose efavirenz pharmacokinetics among Ugandan subjects, using NONMEM. METHODS: Efavirenz plasma concentrations (n = 402) from 121 healthy subjects were quantified by high-performance liquid chromatography. Subjects were genotyped for 30 single nucleotide polymorphisms (SNPs), of which six were novel SNPs in CYP2B6, CYP3A5 and ABCB1. The efavirenz pharmacokinetics was described by a two-compartment model with zero- followed by first-order absorption. RESULTS: Apparent oral clearance (95% confidence interval) was 4 l h l(-1) (3.5, 4.5) in extensive metabolizers. In the final model, incorporating multiple covariates, statistical significance was found only for CYP2B6*6 and CYP2B6*11 on apparent oral clearance as well as ABCB1 (rs3842) on the relative bioavailability. Subjects homozygous for CYP2B6*6 (G516T, A785G) and *11 displayed 21 and 20% lower apparent oral clearance, respectively. Efavirenz relative bioavailability was 26% higher in subjects homozygous for ABCB1 (rs3842). The apparent peripheral volume of distribution was twofold higher in women compared with men. CONCLUSIONS: The model identified the four factors CYP2B6*6, CYP2B6*11, a novel variant allele in ABCB1 (rs3842) and sex as major predictors of efavirenz plasma exposure in a healthy Ugandan population after single-dose administration. Use of mixed-effects modelling allowed the analysis and integration of multiple pharmacogenetic and demographic covariates in a pharmacokinetic population model.
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Röshammar, Daniel,1979Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi,Institute of Neuroscience and Physiology, Department of Pharmacology(Swepub:gu)xroshd
(author)
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Waako, Paul
(author)
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Andersson, Maria
(author)
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Fukasawa, Takashi
(author)
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Milani, LiliUppsala universitet,Institutionen för medicinska vetenskaper
(author)
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Svensson, Jan Olof
(author)
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Ogwal-Okeng, Jasper
(author)
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Gustafsson, Lars LKarolinska Institutet
(author)
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Aklillu, EleniKarolinska Institutet
(author)
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Göteborgs universitetInstitutionen för neurovetenskap och fysiologi, sektionen för farmakologi
(creator_code:org_t)
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In:British journal of clinical pharmacology: Wiley68:5, s. 690-91365-21250306-5251
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Waako, Paul
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