SwePub
Sök i LIBRIS databas

  Utökad sökning

onr:"swepub:oai:gup.ub.gu.se/120176"
 

Sökning: onr:"swepub:oai:gup.ub.gu.se/120176" > A novel polymorphis...

A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans.

Mukonzo, K (författare)
Roshammar, Daniel (författare)
Waako, Paul (författare)
visa fler...
Andersson, Maria (författare)
Fukasawa, Takashi (författare)
Milani, Lili, (författare)
Uppsala universitet, Institutionen för medicinska vetenskaper
Svensson, Olof (författare)
Ogwal-Okeng, Jasper (författare)
Gustafsson, L (författare)
Aklillu, Eleni (författare)
Mukonzo, Jackson K (författare)
Röshammar, Daniel, 1979- (författare)
Göteborgs universitet, Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi, Gothenburg University, Institute of Neuroscience and Physiology, Department of Pharmacology
Svensson, Jan Olof (författare)
visa färre...
Uppsala universitet Medicinska och farmaceutiska vetenskapsområdet. Medicinska fakulteten. Institutionen för medicinska vetenskaper. (creator_code:org_t)
Göteborgs universitet Sahlgrenska akademin. Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi. 
2009
Engelska.
Ingår i: British journal of clinical pharmacology. - 1365-2125. ; 68:5, s. 690-9
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • center dot Efavirenz is metabolized by highly polymorphic enzymes, CYP2B6 and CYP3A. The effect of the different variant alleles on efavirenz population pharmacokinetics has not yet been fully explored. center dot CYP2B6*6 influences efavirenz steady-state pharmacokinetics. Together with sex it explains 11% of the between-subject variability in apparent oral clearance, but predictions could potentially be improved if additional alleles causing reduced drug metabolism were identified. center dot ABCB1 (3435C -> T) may have effect on efavirenz single-dose and steady-state pharmacokinetics. WHAT THIS STUDY ADDS center dot A new polymorphism in ABCB1 gene (rs3842) and CYP2B6*11 in addition to sex and CYP2B6*6 genotype predict efavirenz single-dose pharmacokinetics. center dot A combined population pharmacogenetic/pharmacokinetic modelling approach allows determination and simulation of determinant factors for efavirenz single-dose pharmacokinetics based on data on gender, biochemical variables and genetic factors in relevant genes (a total of 30 SNPs in CYP2B6, ABCB1 and CYP3A4 genes) in Ugandan population. 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 grundvetenskaper -- Farmaceutisk vetenskap (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)

Nyckelord

PHARMACY
FARMACI
ABCB1
CYP2B6
CYP3A5
efavirenz
population pharmacokinetics
Ugandans
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

Publikations- och innehållstyp

art (ämneskategori)
ref (ämneskategori)

Hitta via bibliotek

Till lärosätets databas

 
pil uppåt Stäng

Kopiera och spara länken för att återkomma till aktuell vy