Simvastatin does not influence the intestinal P-glycoprotein and MPR2, and the disposition of talinolol after chronic medication in healthy subjects genotyped for the ABCB1, ABCC2 and SLCO1B1 polymorphisms.
OBJECTIVE
To evaluate whether simvastatin influences (i) the intestinal expression of P-glycoprotein (P-gp) and MRP2, and (ii) the disposition of the beta(1)-selective blocker talinolol, a substrate of these transporter proteins.


METHODS
The disposition of talinolol after intravenous (30 mg) and single or repeated oral administration (100 mg daily) was monitored before and after chronic treatment with simvastatin (40 mg daily) in 18 healthy subjects (10 males, eight females, body mass index 19.0-27.0 kg m(-2)) genotyped for ABCB1, ABCC2 and SLCO1B1 polymorphisms. The steady-state pharmacokinetics of simvastatin was evaluated before and after repeated oral talinolol administration. The duodenal expression of ABCB1 and ABCC2 mRNA before and after simvastatin treatment was quantified using real-time reverse transcriptase-polymerase chain reaction (TaqMan.


RESULTS
Simvastatin did not influence the expression of duodenal ABCB1 and ABCC2. There was no significant pharmacokinetic interaction between simvastatin and talinolol. Duodenal ABCB1 mRNA content was significantly correlated with the AUC(0-infinity) (r = 0.627, P = 0.039) and C(max) (r = 0.718, P = 0.013) of oral talinolol. The ABCB1 and ABCC2 gene polymorphisms did not influence simvastatin and talinolol disposition. The half-life of the latter was significantly shorter in the nine carriers with a SLCO1B1*1b allele compared with the seven subjects with the wild-type SLCO1B1*1a/*1a genotype (12.2 +/- 1.6 h vs. 14.5 +/- 1.4 h, P = 0.01).


CONCLUSIONS
Simvastatin does not influence the intestinal expression of P-gp and MRP2 in man. There was no pharmacokinetic interaction between talinolol and simvastatin during their chronic co-administration to healthy subjects.
Bernsdorf
Annika
A
Department of Clinical Pharmacology of the Peter Holtz Research Centre of Pharmacology and Experimental Therapeutics, University of Greifswald, Germany.
Giessmann
Thomas
T
Modess
Christiane
C
Wegner
Danilo
D
Igelbrink
Stefanie
S
Hecker
Ute
U
Haenisch
Sierk
S
Cascorbi
Ingolf
I
Terhaag
Bernd
B
Siegmund
Werner
W
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis*; D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000328:Adult; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D004347:Drug Interactions; D004386:Duodenum / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007262:Infusions, Intravenous; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D026901:Membrane Transport Proteins / Q000032:analysis*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000032:analysis*; D027361:Organic Anion Transporters / Q000032:analysis; D011110:Polymorphism, Genetic / Q000235:genetics*; D011412:Propanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012333:RNA, Messenger / Q000032:analysis; D019821:Simvastatin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000319:Adrenergic beta-Antagonists; D000924:Anticholesteremic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D011412:Propanolamines; D012333:RNA, Messenger; D019821:Simvastatin; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C503999:SLCO1B1 protein, human; C011550:talinolol