Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism.
BACKGROUND
Both atorvastatin and rifampicin are substrates of OATP1B1 (organic anion transporting polypeptide 1B1) encoded by SLCO1B1 gene. Rifampicin is a potent inhibitor of SLCO1B1 (IC50 1.5 umol/l) and SLCO1B1 521T>C functional genetic polymorphism alters the kinetics of atorvastatin in vivo. We hypothesize that rifampicin might influence atorvastatin kinetics in a SLCO1B1 polymorphism dependent manner.


METHODS
Sixteen subjects with known SLCO1B1 genotypes (6 c.521TT, 6 c.521TC and 4 c.521CC) were divided into 2 groups (atorvastatin-placebo group, n=8; atorvastatin-rifampicin group, n=8) randomly. In this 2-phase crossover study, atorvastatin (40 mg single-oral dose) pharmacokinetics after co-administration of placebo and rifampicin (600 mg single-oral dose) were measured for up to 48 h by liquid chromatography-mass spectrometry (LC-MS). In the third phase, rifampicin (450 mg single-oral dose) pharmacokinetics was measured additionally.


RESULTS
Rifampicin increased atorvastatin plasma concentration in accordance with SLCO1B1 521T>C genotype while the increasing percentage of AUC((0-48)) among c.521TT, c.521TC and c.521CC individuals were 833+/-245% vs 468+/-233% vs 330+/-223% (P=0.007). However, SLCO1B1 521T>C exerted no impact on rifampicin pharmacokinetics (P>0.05).


CONCLUSIONS
These results suggested that rifampicin elevated the plasma concentration of atorvastatin depending on SLCO1B1 genotype and rifampicin pharmacokinetics were not altered by SLCO1B1 genotype.
He
Yi-Jing
YJ
Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, 410078, China.
Zhang
Wei
W
Chen
Yao
Y
Guo
Dong
D
Tu
Jiang-Hua
JH
Xu
Lin-Yong
LY
Tan
Zhi-Rong
ZR
Chen
Bi-Lian
BL
Li
Zhi
Z
Zhou
Gan
G
Yu
Bang-Ning
BN
Kirchheiner
Julia
J
Zhou
Hong-Hao
HH
D000069059:Atorvastatin; D005838:Genotype; D006538:Heptanoic Acids / Q000097:blood*; D006801:Humans; D007700:Kinetics; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011758:Pyrroles / Q000097:blood*; D012293:Rifampin / Q000097:blood* / Q000493:pharmacokinetics; D013936:Thymidine / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D006538:Heptanoic Acids; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D011758:Pyrroles; C503999:SLCO1B1 protein, human; D000069059:Atorvastatin; D013936:Thymidine; D012293:Rifampin