| 1. |
- Bienvenu, Emile, et al.
(författare)
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Frequencies of Single Nucleotide Polymorphisms in Cytochrome P450 Genes in a Rwandan Population: Difference to Other African Populations
- 2013
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Ingår i: Current Pharmacogenomics and Personalized Medicine. - 1875-6921 .- 1875-6913. ; 11:3, s. 237-246
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Tidskriftsartikel (refereegranskat)abstract
- The cytochrome P450 (CYP450) enzymes play a key role for interindividual variability in drug response. No comprehensive pharmacogenetic data are yet available for the Rwandan population in regards to single nucleotide polymorphisms in CYP450s of major importance for personalized medicine. This study investigated the genotype and allele frequencies with respect to relevant SNPs for CYP1A2, CYP2A6, CYP2B6, CYP3A4 and CYP3A5 genes in Rwandan subjects (n=80). Results were compared with data from South African and Cameroonian populations using Pearson's χ2 and Fisher's Exact statistical tests. Genetic variation was observed in 11 out of the 13 SNPs in the above CYP450 genes. There were significant differences in the distribution of the allelic variants when the Rwandan sample was compared to the Cameroonian and the South African groups, with respect to CYP2A6 1093G>A SNP (P=0.0033 and 0.019, respectively) and CYP3A4 -392A>G SNP (P=0.0001 and 0.0084, respectively). The distribution of the CYP1A2-163C>A SNP differed between the Rwandans and the South Africans (P=0.0001), and CYP3A5 6986A>G SNP between the Rwandan and the Cameroonian subjects (P=0.017). The polymorphisms CYP2B6 516G>T and 785A>G did not show significant differences (P>0.05) between the Rwandans, Cameroonians and South Africans in the distribution of the 516T and the 785G variants. This is the first study evaluating the allele and genotype frequencies of these key CYP450 genes in Rwandan subjects. The results demonstrate the need to further characterize individual African populations with respect to genetic variations in order for personalized medicine to be realized among Africans. These data will also help illuminate the future planning of pharmacodynamic studies aimed at associations of these pharmacogenetic variants with drug safety and efficacy in Rwanda. © 2013 Bentham Science Publishers.
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| 2. |
- Johansson, Carl-Christer, et al.
(författare)
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Population pharmacokinetic modeling and deconvolution of enantioselective absorption of eflornithine in the rat.
- 2013
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Ingår i: Journal of pharmacokinetics and pharmacodynamics. - : Springer Science and Business Media LLC. - 1573-8744 .- 1567-567X. ; 40:1, s. 117-28
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Tidskriftsartikel (refereegranskat)abstract
- Enantioselective pharmacokinetics and absorption of eflornithine in the rat was investigated using population pharmacokinetic modeling and a modified deconvolution method. Bidirectional permeability of L- and D-eflornithine was investigated in Caco-2 cells. The rat was administered racemic eflornithine hydrochloride as a single oral dose [40-3,000 mg/kg bodyweight (BW)] or intravenously (IV) (100-2,700 mg/kg BW infused over 60-400 min). Serial arterial blood samples were collected and L- and D-eflornithine were quantitated with a previously published chiral bioanalysis method. The D:L concentration ratio was determined in rat faeces. Intravenous L-and D-eflornithine plasma concentration-time data was analyzed using population pharmacokinetic modeling and described with a 3-compartment pharmacokinetic model with saturable binding to one of the peripheral compartments. Oral plasma concentration-time data was analyzed using a modified deconvolution method accounting for nonlinearities in the eflornithine pharmacokinetics. Clearance was similar for both enantiomers (3.36 and 3.09 mL/min). Oral bioavailability was estimated by deconvolution at 30 and 59% for L- and D-eflornithine. The D:L concentration ratio in feces was 0.49 and the Caco-2 cell permeability was similar for both enantiomers (6-10 × 10(-8) cm/s) with no evident involvement of active transport or efflux. The results presented here suggest that the difference in the bioavailability between eflornithine enantiomers is caused by a stereoselective difference in extent rather than rate of absorption. The presented modified deconvolution method made it possible to account for the non-linear component in the suggested three-compartment pharmacokinetic model thus rapidly estimating eflornithine oral bioavailability.
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| 3. |
- Rekić, Dinko, 1984, et al.
(författare)
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External Validation of the Bilirubin-Atazanavir Nomogram for Assessment of Atazanavir Plasma Exposure in HIV-1-Infected Patients.
- 2013
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Ingår i: The AAPS journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 15:2, s. 308-15
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Tidskriftsartikel (refereegranskat)abstract
- Atazanavir increases plasma bilirubin levels in a concentration-dependent manner. Due to less costly and readily available assays, bilirubin has been proposed as a marker of atazanavir exposure. In this work, a previously developed nomogram for detection of suboptimal atazanavir exposure is validated against external patient populations. The bilirubin nomogram was validated against 311 matching bilirubin and atazanavir samples from 166 HIV-1-infected Norwegian, French, and Italian patients on a ritonavir-boosted regimen. In addition, the nomogram was evaluated in 56 Italian patients on an unboosted regimen. The predictive properties of the nomogram were validated against observed atazanavir plasma concentrations. The use of the nomogram to detect non-adherence was also investigated by simulation. The bilirubin nomogram predicted suboptimal exposure in the patient populations on a ritonavir-boosted regimen with a negative predictive value of 97% (95% CI 95-100). The bilirubin nomogram and monitoring of atazanavir concentrations had similar predictive properties for detecting non-adherence based on simulations. Although both methods performed adequately during a period of non-adherence, they had lower predictive power to detect past non-adherence episodes. Using the bilirubin nomogram for detection of suboptimal atazanavir exposure in patients on a ritonavir-boosted regimen is a rapid and cost-effective alternative to routine measurements of the actual atazanavir exposure in plasma. Its application may be useful in clinical settings if atazanavir concentrations are not available.
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