PMID- 17523051
OWN - NLM
STAT- MEDLINE
DCOM- 20070809
LR  - 20211203
IS  - 0049-8254 (Print)
IS  - 0049-8254 (Linking)
VI  - 37
IP  - 5
DP  - 2007 May
TI  - Gemfibrozil and its glucuronide inhibit the hepatic uptake of pravastatin 
      mediated by OATP1B1.
PG  - 474-86
AB  - When pravastatin (40 mg/day) was co-administered with gemfibrozil (600 mg, 
      b.i.d., 3 days) to man, the AUC of pravastatin increased approximately 2-fold. We 
      have clarified that OATP1B1 is a key determinant of the hepatic uptake of 
      pravastatin in humans. Thus, we hypothesized that gemfibrozil and the main plasma 
      metabolites, a glucuronide (gem-glu) and a carboxylic acid metabolite (gem-M3), 
      might inhibit the hepatic uptake of pravastatin and lead to the elevation of the 
      plasma concentration of pravastatin. Gemfibrozil and gem-glu inhibited the uptake 
      of (14)C-pravastatin by human hepatocytes with K(i) values of 31.7 microM and 
      15.7 microM, respectively and also inhibited pravastatin uptake by 
      OATP1B1-expressing Xenopus laevis oocytes with K(i) values of 15.1 microM and 7.6 
      microM. Additionally, we examined the biliary transport of pravastatin and 
      demonstrated that pravastatin was transported by MRP2 using both human 
      canalicular membrane vesicles (hCMVs) and human MRP2-expressing vesicles. 
      However, gemfibrozil, gem-glu and gem-M3 did not affect the biliary transport of 
      pravastatin by MRP2. Considering the plasma concentrations of gemfibrozil and 
      gem-glu in humans, the inhibition of OATP1B1-mediated hepatic uptake of 
      pravastatin by gem-glu would contribute, at least in part, to the elevation of 
      plasma concentration of pravastatin by the concomitant use of gemfibrozil.
FAU - Nakagomi-Hagihara, R
AU  - Nakagomi-Hagihara R
AD  - Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd, 
      Tokyo, Japan. rienak@sankyo.co.jp
FAU - Nakai, D
AU  - Nakai D
FAU - Tokui, T
AU  - Tokui T
FAU - Abe, T
AU  - Abe T
FAU - Ikeda, T
AU  - Ikeda T
LA  - eng
PT  - Journal Article
PL  - England
TA  - Xenobiotica
JT  - Xenobiotica; the fate of foreign compounds in biological systems
JID - 1306665
RN  - 0 (ABCC2 protein, human)
RN  - 0 (Anticholesteremic Agents)
RN  - 0 (Glucuronides)
RN  - 0 (Hypolipidemic Agents)
RN  - 0 (Liver-Specific Organic Anion Transporter 1)
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (Multidrug Resistance-Associated Protein 2)
RN  - 0 (Multidrug Resistance-Associated Proteins)
RN  - 0 (Organic Anion Transporters)
RN  - 0 (SLCO1B1 protein, human)
RN  - KXO2KT9N0G (Pravastatin)
RN  - Q8X02027X3 (Gemfibrozil)
SB  - IM
MH  - Animals
MH  - Anticholesteremic Agents/chemistry/*metabolism
MH  - Drug Interactions
MH  - Female
MH  - Gemfibrozil/chemistry/*pharmacology
MH  - Glucuronides/chemistry/*pharmacology
MH  - Hepatocytes/drug effects/*metabolism
MH  - Humans
MH  - Hypolipidemic Agents/chemistry/*pharmacology
MH  - Kinetics
MH  - Liver-Specific Organic Anion Transporter 1
MH  - Membrane Transport Proteins/metabolism
MH  - Multidrug Resistance-Associated Protein 2
MH  - Multidrug Resistance-Associated Proteins/metabolism
MH  - Organic Anion Transporters/*metabolism
MH  - Pravastatin/chemistry/*metabolism
MH  - Transport Vesicles/drug effects/metabolism
MH  - Xenopus laevis
EDAT- 2007/05/25 09:00
MHDA- 2007/08/10 09:00
CRDT- 2007/05/25 09:00
PHST- 2007/05/25 09:00 [pubmed]
PHST- 2007/08/10 09:00 [medline]
PHST- 2007/05/25 09:00 [entrez]
AID - 778314831 [pii]
AID - 10.1080/00498250701278442 [doi]
PST - ppublish
SO  - Xenobiotica. 2007 May;37(5):474-86. doi: 10.1080/00498250701278442.