Clinical Significance of Differences in Bioavailability of Medroxyprogesterone Acetate Preparations

Abstract

Synthetic progestational agents first became widely available in the early 1960s and were investigated for use in patients with hormoneresponsive tumours, i.e. breast, kidney, uterine and prostate cancer. A range of different preparations was available, but their clinical use was limited by side effects including nausea and vomiting, masculinisation, Cushingoid effects and liver damage (Stoll 1967). An early study (Stoll 1967) of 6 orally active agents, including medroxyprogesterone acetate (MPA), concluded that all were active in breast cancer and that resistance to one agent did not necessarily imply resistance to others. However, response rates were disappointing, ranging from 16 to 22%, and over the ensuing years the use of medroxyprogesterone acetate was confined mainly to endometrial and kidney cancers. High-Dose MPA in Carcinoma o/the BreastInterest in medroxyprogesterone acetate in carcinoma of the breast was rekindled by the work of Pannuti and colleagues, who investigated its maximum tolerated intramuscular dose;and reported greatly increased objective response rates of 44% with intramuscular doses of 1500mg daily for 30 days (Pannuti et al. 1978). Although the initial studies were troubled by a high incidence of sterile abscess formation at the injection site, investigators were impressed by a feeling of well being associated with increased appetite and weight gain due to the drug, which were thought to be of benefit to the patient. Prompt improvement of bone pain was also noted for many patients. These results implied a dose-response effect for medroxyprogesterone acetate, which became accepted on the basis of the historical results (Ganzina 1979). It might thus be assumed that differing bioavailability of medroxyprogesterone acetate preparations could be of significance. When radioimmunoassay (RIA) techniques became available to measure serum medroxyprogesterone acetate concentrations, attempts were made to rationalise dosage schedules and elucidate the pharmacokinetics of the drug.

Metabolism of medroxyprogesterone acetate (MPA) via CYP enzymes in vitro and effect of MPA on bleeding time in female rats in dependence on CYP activity in vivo

“…MPA exhibits low oral bioavailability ( < 10%), which may be due to numerous factors, including metabolism in the intestinal mucosa and liver (Stockdale and Rostom, 1989). In fact, MPA has been shown to undergo extensive and rapid metabolism in humans (Stockdale and Rostom, 1989) and in experimental animals (Rautio et al, 1985).…”

“…In fact, MPA has been shown to undergo extensive and rapid metabolism in humans (Stockdale and Rostom, 1989) and in experimental animals (Rautio et al, 1985). Recently, we reported that MPA was metabolized by cytochrome P450 3A4 (CYP3A4) in human liver microsomes (Kobayashi et al, 2000).…”