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Clin Pharmacokinet. 1990 Jun;18(6):472-84.

Pharmacokinetic drug interactions with oral contraceptives.

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Department of Pharmacology and Therapeutics, University of Liverpool, England.


Oral contraceptive steroids are used by an estimated 60 to 70 million women world-wide. Over the past 20 years there have been both case reports and clinical studies on the topic of drug interactions with these agents. Some of the interactions are of definite therapeutic relevance, whereas others can be discounted as being of no clinical significance. Pharmacological interactions between oral contraceptive steroids and other compounds may be of 2 kinds: (a) drugs may impair the efficacy of oral contraceptive steroids, leading to breakthrough bleeding and pregnancy (in a few cases, the activity of the contraceptive is enhanced); (b) oral contraceptive steroids may interfere with the metabolism of other drugs. A number of anticonvulsants (phenobarbital, phenytoin, carbamazepine) are enzyme-inducing agents and thereby increase the clearance of the oral contraceptive steroids. Valproic acid has no enzyme-inducing properties, and thus women on this anticonvulsant can rely on their low dose oral contraceptive steroids for contraceptive protection. Researchers are now beginning to unravel the molecular basis of this interaction, with evidence of specific forms of cytochrome P450 (P450IIC and IIIA gene families) being induced by phenobarbital. Rifampicin, the antituberculous drug, also induces a cytochrome P450 which is a product of the P450IIIA gene subfamily. This isozyme is one of the major forms involved in 2-hydroxylation of ethinylestradiol. Broad spectrum antibiotics have been implicated in causing pill failure; case reports document the interaction, and general practitioners are convinced that it is real. The problem remains that there is still no firm clinical pharmacokinetic evidence which indicates that blood concentrations of oral contraceptive steroids are altered by antibiotics. However, perhaps this should not be a surprise, given that the incidence of the interaction may be very low. It is suggested that an individual at risk will have a low bioavailability of ethinylestradiol, a large enterohepatic recirculation and gut flora particularly susceptible to the antibiotic being used. Two drugs, ascorbic acid (vitamin C) and paracetamol (acetaminophen), give rise to increased blood concentrations of ethinylestradiol due to competition for sulphation. The interactions could have some significance to women on oral contraceptive steroids who regularly take high doses of either drug. Although on theoretical grounds adsorbents (e.g. magnesium trisilicate, aLuminium hydroxide, activated charcoal and kaolin) could be expected to interfere with oral contraceptive efficacy, there is no firm evidence that this is the case. Similarly, there is no evidence that smoking alters the pharmacokinetics of oral contraceptive steroids. These agents are now well documented as being able to alter the pharmacokinetics of other concomitantly administered drugs.(ABSTRACT TRUNCATED AT 400 WORDS).


The pharmacokinetics and clinical significance of the major drug interactions seen with oral contraceptives are reviewed, both drugs interfering with pill efficacy, and situations where pills interfere with action of other drugs. Drugs affecting contraceptive efficacy include anticonvulsants, antibiotics, rifampicin, griseofulvin, ascorbic acid, and acetaminophen. Phenytoin is the most common anticonvulsant reported to cause contraceptive failure. It as been established by measurements of steady-state ethinyl estradiol levels, sex hormone binding globulin levels, and pharmacokinetic drug concentration curves that both ethinyl estradiol and levonorgestrel levels are decreased during phenytoin and carbamazepine intake. Induction of certain cytochrome P450 isozymes is probably responsible. Neither the causation or even the existence of drug interaction with antibiotics is definitely known, although case reports of pregnancies abound. Rifampicin is an exception, where enzyme induction clearly occurs. Ascorbic acid and acetaminophen are atypical for increasing the therapeutic effect of ethinyl estradiol. The effect of benzodiazepines depends on the type of drug metabolism: drugs oxidized and nitroreduced, e.g. chlordiazepoxide, alprazolam, diazepam, and nitrazepam, exhibit reduced clearance during pill intake. Clearance of cyclosporin, prednisolone, alcohol, caffeine and theophylline are also slowed by orals. Pills accelerate clearance of salicylic acid and morphine.

[Indexed for MEDLINE]

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