Comprehensive Pharmacogenomic Study Reveals an Important Role of UGT1A3 in Montelukast Pharmacokinetics

Lapatto‐Reiniluoto

et al. 2018

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Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, crossover study in 12 healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel. Clopidogrel, but not ritonavir, increased the geometric mean AUC of dasabuvir 4.7-fold; range 2.0-10.1-fold (P = 8·10 ), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC 3.9-fold; range 2.1-7.9-fold (P = 2·10 ), compared with ritonavir alone. Ritonavir decreased the AUC of clopidogrel active metabolite by 51% (P = 0.0001), and average platelet inhibition from 51% without ritonavir to 31% with ritonavir (P = 0.0007). In conclusion, clopidogrel markedly elevates dasabuvir concentrations, and patients receiving ritonavir are at risk for diminished clopidogrel response.

Section: Discussionmentioning

confidence: 99%

Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel

Itkonen

Lapatto‐Reiniluoto

et al. 2018

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“…Genomic DNA was extracted from ethylenediaminetetraacetic acid blood samples using the Maxwell 16 LEV Blood DNA Kit on a Maxwell 16 Research automated nucleic acid extraction system (Promega, Madison, WI). A total of 379 pharmacokinetic genes ± 20 kb were completely sequenced in the study participants using targeted massive parallel sequencing at the Technology Centre at Institute for Molecular Medicine Finland (Helsinki, Finland) . A total of 46,064 SNVs with minor allele frequency ≥ 0.05 were included in the statistical analysis.…”

Section: Methodsmentioning

confidence: 99%

“…A total of 379 pharmacokinetic genes ± 20 kb were completely sequenced in the study participants using targeted massive parallel sequencing at the Technology Centre at Institute for Molecular Medicine Finland (Helsinki, Finland). 42,43 A total of 46,064 SNVs with minor allele frequency ≥ 0.05 were included in the statistical analysis.…”

Section: Dna Sequencing and Genotypingmentioning

confidence: 99%

Enantiospecific Pharmacogenomics of Fluvastatin

Hirvensalo

Neuvonen

et al. 2019

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The aim of this study was to investigate how variability in multiple genes related to pharmacokinetics affects fluvastatin exposure. We determined fluvastatin enantiomer pharmacokinetics and sequenced 379 pharmacokinetic genes in 200 healthy volunteers. CYP2C9*3 associated with significantly increased area under the plasma concentration‐time curve (AUC) of both 3R,5S‐fluvastatin and 3S,5R‐fluvastatin (by 67% and 94% per variant allele copy, P = 3.77 × 10−9 and P = 3.19 × 10−12). In contrast, SLCO1B1 c.521T>C associated with increased AUC of active 3R,5S‐fluvastatin only (by 34% per variant allele copy; P = 8.15 × 10−8). A candidate gene analysis suggested that CYP2C9*2 also affects the AUC of both fluvastatin enantiomers and that SLCO2B1 single‐nucleotide variations may affect the AUC of 3S,5R‐fluvastatin. Thus, SLCO transporters have enantiospecific effects on fluvastatin pharmacokinetics in humans. Genotyping of both CYP2C9 and SLCO1B1 may be useful in predicting fluvastatin efficacy and myotoxicity.

“…In order to verify genotype calls and to supplement missing data, all study participants were genotyped with TaqMan genotyping assays on a QuantStudio 12K Flex Real-Time PCR System for the UGT1A rs13401281, rs3821242, rs4663969, rs6715325, rs6431625, rs45449995, rs4148323, and rs3064744 sequence variations (Thermo Fisher Scientific, Waltham, MA). 18,22 Call identity with sequencing data was 99.5% for rs6715325 and 100% for all other SNVs. In case of discordant results, genotypes obtained by sequencing were used in the statistical analysis.…”

Section: Dna Sequencing and Genotypingmentioning

confidence: 97%

“…A total of 379 pharmacokinetic genes, comprising phase I and II metabolizing enzymes, influx and efflux drug transporters, and regulatory proteins, were selected to be studied. [18][19][20] These genes ± 20 kb, were completely sequenced in the study participants using targeted massive parallel sequencing at the Technology Centre at Institute for Molecular Medicine Finland (Helsinki, Finland). 21 NEBNext DNA Sample Prep protocol (New England BioLabs, Ipswich, MA) was used for library preparation and the NimbleGen SeqCap EZ Choice protocol (Roche Sequencing, Pleasanton, CA) for target enrichment capture.…”

Section: Dna Sequencing and Genotypingmentioning

confidence: 99%

UGT1A3 and Sex Are Major Determinants of Telmisartan Pharmacokinetics—A Comprehensive Pharmacogenomic Study

Hirvensalo

Launiainen

et al. 2020

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To investigate how variability in multiple pharmacokinetic genes associates with telmisartan exposure, we determined telmisartan single‐dose (40 mg) pharmacokinetics and sequenced 379 genes in 188 healthy volunteers. Intronic UGT1A variants showed the strongest associations with the area under the plasma concentration‐time curve from zero hours to infinity (AUC0–∞) and peak plasma concentration (Cmax) of telmisartan. These variants were strongly linked with the increased function UGT1A3*2 allele, suggesting that it is the causative allele underlying these associations. In addition, telmisartan plasma concentrations were lower in men than in women. The UGT1A3*2 was associated with a 64% and 63% reduced AUC0‐∞ of telmisartan in UGT1A3*2 heterozygous and homozygous men, respectively (P = 1.21 × 10−16 and 5.21 × 10−8). In women, UGT1A3*2 heterozygosity and homozygosity were associated with 57% (P = 1.54 × 10−11) and 72% (P = 3.31 × 10−15) reduced AUC0‐∞, respectively. Furthermore, a candidate gene analysis suggested an association of UGT1A3*3 and the SLCO1B3 c.767G>C missense variant with telmisartan pharmacokinetics. A genotype score, which reflects the effects of sex and genetic variants on telmisartan AUC0–∞, associated with the effect of telmisartan on diastolic blood pressure. These data indicate that sex and UGT1A3 are major determinants and suggest a role for OATP1B3 in telmisartan pharmacokinetics.