Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol: a new look at an old drug.
17alpha-Ethinylestradiol (EE) is widely used as the estrogenic component of oral contraceptives (OC). In vitro and in vivo metabolism studies indicate that EE is extensively metabolised, primarily via intestinal sulfation and hepatic oxidation, glucuronidation and sulfation. Cytochrome P450 (CYP)3A4-mediated EE 2-hydroxylation is the major pathway of oxidative metabolism of EE. For some time it has been known that inducers of drug-metabolising enzymes (such as the CYP3A4 inducer rifampicin [rifampin]) can lead to breakthrough bleeding and contraceptive failure. Conversely, inhibitors of drug-metabolising enzymes can give rise to elevated EE plasma concentrations and increased risks of vascular disease and hypertension. In vitro studies have also shown that EE inhibits a number of human CYP enzymes, such as CYP2C19, CYP3A4 and CYP2B6. Consequently, there are numerous reports in the literature describing EE-containing OC formulations as perpetrators of pharmacokinetic drug interactions. Because EE may participate in multiple pharmacokinetic drug interactions as either a victim or perpetrator, pharmaceutical companies routinely conduct clinical drug interaction studies with EE-containing OCs when evaluating new chemical entities in development. It is therefore critical to understand the mechanisms underlying these drug interactions. Such an understanding can enable the interpretation of clinical data and lead to a greater appreciation of the profile of the drug by physicians, clinicians and regulators. This article summarises what is known of the drug-metabolising enzymes and transporters governing the metabolism, disposition and excretion of EE. An effort is made to relate this information to known clinical drug-drug interactions. The inhibition and induction of drug-metabolising enzymes by EE is also reviewed.
Zhang
Hongjian
H
Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA. hongjian.zhang@bms.com
Cui
Donghui
D
Wang
Bonnie
B
Han
Yong-Hae
YH
Balimane
Praveen
P
Yang
Zheng
Z
Sinz
Michael
M
Rodrigues
A David
AD
D001711:Biotransformation; D003276:Contraceptives, Oral / Q000493:pharmacokinetics* / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D004997:Ethinyl Estradiol / Q000493:pharmacokinetics* / Q000494:pharmacology; D018565:Food-Drug Interactions; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D008954:Models, Biological; D010084:Oxidation-Reduction; D011372:Progestins / Q000494:pharmacology; D015238:Sulfotransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013463:Sulfuric Acid Esters / Q000378:metabolism
D003276:Contraceptives, Oral; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D020719:Glucuronides; D007527:Isoenzymes; D026901:Membrane Transport Proteins; D011372:Progestins; D013463:Sulfuric Acid Esters; D004997:Ethinyl Estradiol; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D015238:Sulfotransferases