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A novel polymorphis...
A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans.
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Mukonzo, Jackson K (författare)
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- Röshammar, Daniel, 1979 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi,Institute of Neuroscience and Physiology, Department of Pharmacology
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Waako, Paul (författare)
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Andersson, Maria (författare)
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Fukasawa, Takashi (författare)
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- Milani, Lili (författare)
- Uppsala universitet,Institutionen för medicinska vetenskaper
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Svensson, Jan Olof (författare)
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Ogwal-Okeng, Jasper (författare)
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- Gustafsson, Lars L (författare)
- Karolinska Institutet
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- Aklillu, Eleni (författare)
- Karolinska Institutet
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(creator_code:org_t)
- 2009-08-07
- 2009
- Engelska.
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Ingår i: British journal of clinical pharmacology. - : Wiley. - 1365-2125 .- 0306-5251. ; 68:5, s. 690-9
- Relaterad länk:
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https://bpspubs.onli...
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- Adult
- African Continental Ancestry Group
- genetics
- Anti-HIV Agents
- pharmacokinetics
- Benzoxazines
- pharmacokinetics
- Dose-Response Relationship
- Drug
- Female
- Humans
- Male
- Models
- Biological
- Models
- Genetic
- Polymorphism
- Genetic
- genetics
- Sex Factors
- Uganda
- Young Adult
- ABCB1
- PHARMACY
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Mukonzo, Jackson ...
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Röshammar, Danie ...
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Waako, Paul
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Andersson, Maria
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Fukasawa, Takash ...
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Milani, Lili
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visa fler...
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Svensson, Jan Ol ...
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Ogwal-Okeng, Jas ...
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Gustafsson, Lars ...
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Aklillu, Eleni
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visa färre...
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Göteborgs universitet
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Karolinska Institutet
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Uppsala universitet