J. Scavone, D. Greenblatt, G. Blyden
2004
Citations
0
Influential Citations
7
Citations
Journal
European Journal of Clinical Pharmacology
Abstract
Acetaminophen is biotransformed by glucuronide and sulfate conjugation and is used as an index compound to evaluate factors that may potentially influence drug conjugation capacity [1]. Conjugated estrogens are commonly used for the treatment of vasomotor symptoms associated with menopause, as replacement therapy in hypergonadism, and for estrogen-deficiency-induced osteoporosis. Because the metabolic clearance of several drugs is altered by low-dose estrogen-containing oral contraceptive preparations and conjugated estrogens, the possibility of a pharmacokinetic interaction exists between conjugated estrogens and drugs that undergo glucuronide and sulfate conjugation [2-9]. Thus, we evaluated the effect of chronic conjugated estrogen use on acetaminophen pharmacokinetics. Thirty healthy female volunteers participated after giving written informed consent. Twelve of the women had been taking a conjugated estrogen preparation for at least 3 or more months prior to the study for at least 3 or 4 weeks per month. A control group consisted of 18 women were not taking conjugated estrogens. The two groups were matched as closely as possible for age and body weight (Table 1). All subjects were healthy, active, ambulatory adults with no history of medical disease and who were taking no other medications except as described above. Acetaminophen (650 mg) was administered by constant intravenous infusion over a 5-rain period [10]. Venous blood samples were drawn from the contralateral arm into heparinized tubes at multiple time points during 24 h after drug administration. Samples were centrifuged and the plasma was separated and stored at 20 °C until the time of assay. Concentrations of acetaminophen in all samples were determined by high-presgure liquid chromatography [10]. Pharmacokinetic variables for acetaminophen were determined by iterative nonlinear least-squares regression analysis [11]. Differences in acetaminophen kinetic variables between control subjects and conjugated estrogen recipients were analyzed with an unpaired Student's t-test. There were no significant differences between groups in acetaminophen volume of distribution, elimination half-life, or clearance (Table 1). When only the non-smokers in each group were analyzed, there still was no significant difference between controls and conjugated estrogen users in acetaminophen clearance. Conjugated estrogens and low-dose estrogen-containing oral contraceptive preparations have a variable effect on metabolic clearance of drugs biotransformed by oxidation and conjugative mechanisms [2-9]. Since prophylactic conjugated estrogen use may prevent osteoporosis and associated vertebral and various osteoporotic fractures, it is important to identify and quantitate any changes in drug metabolizing activity that may be associated with conjugated estrogen therapy. In this study, conjugated estrogen use did not alter acetaminophen pharmacokinetics, although low-dose estrogen-containing oral contraceptives has been reported to enhance the metabo-