Impact of efavirenz on intestinal metabolism and transport: insights from an interaction study with ezetimibe in healthy volunteers

Autor: Heyo K. Kroemer, Markus Keiser, W. Siegmund, J Mostertz, Stefan Oswald, A Nassif, Dieter Lütjohann, Andrea Hubeny, Christiane Modess, A Ulrich, Evan T. Ogburn, H E Meyer zu Schwabedissen, D Runge, J Jia, M Marinova, Zeruesenay Desta
Rok vydání: 2012
Předmět:
Cyclopropanes
Male
Organic anion transporter 1
Gene Expression
Organic Anion Transporters
HIV Infections
Pharmacology
Intestinal absorption
chemistry.chemical_compound
immune system diseases
Cytochrome P-450 CYP3A
Pharmacology (medical)
Drug Interactions
Glucuronosyltransferase
Intestinal Mucosa
P-glycoprotein
media_common
Cell Line
Transformed
biology
Liver-Specific Organic Anion Transporter 1
Multidrug resistance-associated protein 2
Anticholesteremic Agents
virus diseases
Multidrug Resistance-Associated Protein 2
Intestines
Liver
Alkynes
Multidrug Resistance-Associated Proteins
medicine.drug
Drug
Adult
Efavirenz
ATP Binding Cassette Transporter
Subfamily B
media_common.quotation_subject
Hypercholesterolemia
Article
Cell Line
Young Adult
Dogs
Ezetimibe
Pharmacokinetics
medicine
Animals
Humans
ATP Binding Cassette Transporter
Subfamily B
Member 1
RNA
Messenger
Biological Transport
Benzoxazines
HEK293 Cells
chemistry
Intestinal Absorption
biology.protein
Azetidines
Zdroj: Clinical pharmacology and therapeutics. 91(3)
ISSN: 1532-6535
Popis: Hypercholesterolemia frequently occurs in patients treated with efavirenz who cannot be treated adequately with statins because of drug interactions. These patients may benefit from cholesterol-lowering therapy with ezetimibe. This study determined the influence of single-dose and multiple-dose efavirenz (400 mg/day for 9 days) on the pharmacokinetics and sterol-lowering of ezetimibe (10 mg) in 12 healthy subjects. In addition, the influence of efavirenz on genome-wide intestinal expression and in vitro function of ABCB1, ABCC2, UGT1A1, and OATP1B1 was studied. Efavirenz (multiple dose) had no influence on the pharmacokinetics and lipid-lowering functions of ezetimibe. Intestinal expression of enzymes and transporters (e.g., ABCB1, ABCC2, and UGT1A1) was not affected by chronic efavirenz. Efavirenz (single dose) slightly increased ezetimibe absorption and markedly decreased exposure to ezetimibe-glucuronide (single dose and multiple dose), which may be explained by inhibition of UGT1A1 and ABCB1 (in vitro data). Ezetimibe had no effect on the disposition of efavirenz. Consequently, ezetimibe may be a safe and efficient therapeutic option in patients with HIV infection.
Databáze: OpenAIRE
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