Pharmacokinetic profile of atorvastatin in relation to SLCO1B1 C.521T>C and C.388A> variants in healthy volunteers

Daka, Arlinda and Dimovski, Aleksandar and Kapedanovska, Aleksandra and Vavlukis, Marija and Eftimov, Aleksandar and Labacevski, Nikola and Jakovski, Kristijan and Matevska, Geshovska, M. and Nebija, D. and Mladenovska, Kristina (2015) Pharmacokinetic profile of atorvastatin in relation to SLCO1B1 C.521T>C and C.388A> variants in healthy volunteers. In: 5th Croartian Congress on Pharmacy, 21-24 May 2015, Rovinj, Croatia.

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Abstract

OATP1B1 is an influx transporter known to be implicated as important determinant of the intestinal absorption and hepatobiliary clearance of hydrophilic statins, such as atorvastatin. Several sequence variations have been discovered in the SLCO1B1 gene encoding OATP1B1, with some of them, such as c.388A>G (p.Asn130Asp) and c.521T>C (Val174Ala) associated with increased and reduced OATP1B1 activity, respectively. The aim of the study was to investigate the effects of these two SLCO1B1 SNPs on the pharmacokinetics of atorvastatin. Twenty three healthy Macedonian volunteers were genotyped for these two SNPs using TaqMan allelic discrimination assay. After ingestion of a single dose of 80 mg, the plasma concentrations of atorvastatin were measured for 48 h using LC-MS-MS and the Cmax, Tmax, t1/2, kel, MRT, Vd, CL, AUC0-48h and AUC0-~ were determined. Allele frequencies of the variants were in Hardy-Weinberg Equilibrium, with 39 and 15% for c.388A>G and c.521T>C, respectively. Low correlation between this SNP pair (R2=0.137; D’=0.700) was observed. No significant differences in the kel, t1/2, Cmax, Tmax, AUC0-48h, AUC0-~, MRT, Vd and CL between the carriers of different c.388A>G genotypes were observed. Subject with a c.521CC genotype had markedly higher values for Cmax and AUC0-48h, 140 and 67% respectively, in comparison with the carriers of the c.521TT genotype. These differences lacked statistical significance due to the size of the sample. In addition, the effects of SLCO1B1 diplotypes on pharmacokinetic parameters were investigated comparing the effects of *15 non-carriers (n=17) and *15 heterozygotes (n=6), as *15 homozygotes were not identified in the study. The dominant effect of the c.521T>C SNP was confirmed. Marginal statistical differences were observed in Cmax, AUC0-48h, AUC0-~ and CL, with Cmax and AUC0-~ 45% (p=0.062) and 38% (n=0.09) higher, and CL 30% (p=0.07) lower in *15 heterozygotes/carriers of c.521C allele. Additional studies, with a large sample size are needed to confirm this finding.

Item Type: Conference or Workshop Item (Other)
Subjects: Medical and Health Sciences > Basic medicine
Divisions: Faculty of Medical Science
Depositing User: Marija Vavlukis
Date Deposited: 23 Jun 2015 08:20
Last Modified: 23 Jun 2015 08:20
URI: http://eprints.ugd.edu.mk/id/eprint/13209

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