Disposition and sterol-lowering effect of ezetimibe are influenced by single-dose coadministration of rifampin, an inhibitor of multidrug transport proteins.
OBJECTIVE
The disposition and sterol-lowering effect of ezetimibe are associated with long-lasting enterosystemic circulation, which is initiated by secretion of ezetimibe and its glucuronide via intestinal P-glycoprotein (P-gp) (ABCB1) and the multidrug resistance-associated protein 2 (MRP2) (ABCC2) into gut lumen. Hepatic uptake and secretion may contribute to recycling. To obtain deeper insight into the intestinal and hepatic processes, the disposition of ezetimibe was studied in the presence of rifampin (INN, rifampicin), a modulator of P-gp, MRP2, and hepatic organic anion (uptake) transporting polypeptides (OATPs) (SLCOs).


METHODS
The disposition of ezetimibe (20 mg orally) alone and after coadministration of rifampin (600 mg orally) was measured in a crossover study of 8 healthy subjects with the SLCO1B1 *1a/*1a genotype. Concentrations of ezetimibe and its glucuronide in serum, urine, and feces, as well as cholesterol, lathosterol, and the plant sterols campesterol and sitosterol in serum, were quantified by use of liquid chromatography and gas chromatography with mass spectrometric detection.


RESULTS
After rifampin administration, the maximum serum concentrations of ezetimibe and its glucuronide were significantly elevated (12.0+/-4.20 ng/mL versus 4.67+/-2.72 ng/mL, P=.017, and 282+/-73.8 ng/mL versus 107+/-35.3 ng/mL, P=.012, respectively). The area under the curve of ezetimibe was not affected (102+/-37.6 ng.h/mL versus 140+/-86.3 ng.h/mL, P=not significant), whereas that of the glucuronide was markedly increased (2150+/-687 ng.h/mL versus 1030+/-373 ng.h/mL, P=.012). Renal clearance remained unchanged. Fecal excretion of ezetimibe was markedly decreased (7.6+/-2.2 mg versus 10.4+/-1.8 mg, P=.036), whereas renal excretion of the glucuronide was strongly elevated (4.8+/-1.9 mg versus 2.0+/-1.2 mg, P=.049) after coadministration. The onset of a significant sterol-lowering effect of ezetimibe was significantly shortened by rifampin coadministration.


CONCLUSIONS
Coadministration of rifampin increases the maximum serum concentrations of ezetimibe but reduces its enterosystemic recycling, most likely by inhibition of the secretion of ezetimibe and its glucuronide via P-gp and MRP2.
Oswald
Stefan
S
Department of Clinical Pharmacology, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany.
Giessmann
Thomas
T
Luetjohann
Dieter
D
Wegner
Danilo
D
Rosskopf
Dieter
D
Weitschies
Werner
W
Siegmund
Werner
W
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000235:genetics; D000284:Administration, Oral; D000328:Adult; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D001384:Azetidines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D002784:Cholesterol / Q000031:analogs & derivatives / Q000097:blood; D002849:Chromatography, Gas / Q000379:methods; D002853:Chromatography, Liquid / Q000379:methods; D018592:Cross-Over Studies; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000069438:Ezetimibe; D005243:Feces / Q000737:chemistry; D005260:Female; D005838:Genotype; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters / Q000235:genetics; D010840:Phytosterols / Q000097:blood; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012855:Sitosterols / Q000097:blood; D013997:Time Factors; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D000924:Anticholesteremic Agents; D001384:Azetidines; D002784:Cholesterol; D004791:Enzyme Inhibitors; D000069438:Ezetimibe; D020719:Glucuronides; D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters; D010840:Phytosterols; D012293:Rifampin; D012855:Sitosterols; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C000715087:ABCC2 protein, human; C503999:SLCO1B1 protein, human; C021273:campesterol; C025473:gamma-sitosterol; C001521:lathosterol