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

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

An insight into an intriguing oxidative biotransformation pathway of 5-O-caffeoylquinic acid by a gut bacterium

International audienceMicrobiota is known to play a pivotal role in generating bioavailable and bioactive low-molecular-weight metabolites from dietary polyphenols. 5-O-caffeoylquinic acid (5-CQA), one of the main polyphenols found in human diet, was submitted to a resting cell biotransformation study using three gut bacteria species Lactobacillus reuteri, Bacteroides fragilis and Bifidobacterium longum. These bacteria were selected according to their belonging to the main phyla found in human gut microbiota. Our study highlighted the ability of only one of the strains studied, L. reuteri, to bioconverse 5-CQA into various metabolites due to the expression of the cinnamoyl esterase enzyme as the first step. Interestingly, one known natural compound, esculetin, was described for the first time as a 5-CQA-derived metabolite after conversion by a gut bacterium, the other metabolites had already been reported. This evidence highlighted an interesting oxidative pathway occurring in vivo by intestinal microbiota leading to esculetin. This molecule was also identified after electrochemical and enzymatic oxidations of caffeic acid. The oxidation capacity of L. reuteri led to less diverse metabolites in comparison to those obtained either electrochemically and enzymatically where dimers and trimers were reported. Thus, esculetin may have interesting and benefical biological effects on gut microbiota, which should be further evaluated. Novel synbiotics could be formulated from the association of L. reuteri with 5-CQA