Browsing by Subject "fluvastatin"

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  • Hirvensalo, Päivi; Tornio, Aleksi; Neuvonen, Mikko; Kiander, Wilma; Kidron, Heidi; Paile-Hyvärinen, Maria; Tapaninen, Tuija; Backman, Janne T.; Niemi, Mikko (2019)
    Abstract 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- 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 (SNVs) 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. This article is protected by copyright. All rights reserved.
  • Kahma, Helinä (Helsingfors universitet, 2014)
    Active transport processes in the basolateral (sinusoidal) membrane of hepatocytes have an important role in the hepatic clearance and overall disposition for several types of drugs. Organic anion transporting polypeptides (OATPs) expressed in the sinusoidal membrane have been shown to mediate the sodium-independent hepatic uptake of broad range of drugs and they have been associated with clinically relevant drug-drug interactions (DDIs) and genetic polymorphisms. The literature review focuses on sinusoidal OATP transporters and on the pharmacokinetic effects of OATP-mediated hepatic uptake. In addition, current methods to investigate the interactions between drugs and transporters are discussed, with the emphasis on methods applicable to study uptake transporters. The aim of the experimental part of the master's thesis was to determine if two clinically used drugs, entacapone and fluvastatin, are actively transported from blood into rat and human hepatocytes, and to assess the role of OATP transporters in the hepatic uptake of the drugs in comparison with known OATP substrates, estrone 3-sulfate (E3S) and taurocholic acid and broad OATP inhibitor rifamycin SV. The uptake kinetics of compounds of interest were determined in freshly isolated and cryopreserved rat hepatocytes and in cryopreserved human hepatocytes using the oil-spin method. Uptake clearances (CLuptake) via active uptake (CLactive) and passive diffusion (Pdiff) were calculated from the initial uptake data over a 1 - 200 µM and 1 - 50 µM concentration range for entacapone and fluvastatin, respectively. The half-maximal inhibitor concentration (IC50) of E3S uptake transport was determined for entacapone in a competitive uptake experiment over a 10 - 400 µM concentration range. Fluvastatin uptake showed active saturable transport kinetics in rat hepatocytes with a Km value of 6 µM, whereas entacapone uptake in rat hepatocytes was somewhat linear and did not inhibit E3S uptake at clinically significant concentrations, with an IC50 value of 240 µM. Significantly lower hepatic uptake of taurocholate and entacapone was observed between rat and human hepatocytes, indicating species differences in hepatic uptake processes, although cryopreservation may have had an effect on the noticed difference. The results suggest that murine Oatp transporters do not have a significant contribution to hepatic uptake of entacapone. However, this should be confirmed with future studies with more repetitions and a reliable quantification method.