Clinical Pharmacokinetics of Oral Contraceptive Steroids

Abstract

Oral contraceptive steroids are of 2 types: oestrogens, of which ethinyloestradiol is the most important, and progestagens, of which levonorgestrel and norethisterone are the most commonly used. All these steroids can be measured by a number of analytical techniques but there is little doubt that radioimmunoassay is the most convenient. All. the steroids are well absorbed in humans but while levonorgestrel is completely bioavailable, norethisterone has an average bioavailability of 70%. Ethinyloestradiol, too, is subject to presystemic metabolism with a mean bioavailability of 40 to 45%. The main site of presystemic metabolism is the gut wall, with the production of ethinyloestradiol sulphate. The progestagens norethynodrel, ethynodiol diacetate and lynoestrenol are quantitatively metabolised to norethisterone.The pharmacokinetics of the contraceptive steroids are best described by a 2-compartment open model. The terminal plasma half-life of levonorgestrel varies from 11 to 45 hours and of norethisterone from 5 to 14 hours. The Ii-phase half-life of ethinyloestradiol varies from 6 to 20 hours. The apparent volume of distribution of these contraceptive steroids (after intravenous administration) is between 1.5 and 4.3 Llkg. During long term treatment with oral contraceptive steroids, steady-state plasma concentrations of ethinyloestradiol (24 hours after administration) are between 10 and 200 pg/m!. Plasma concentrations of norethisterone and levonorgestrel at steady-state are higher than predicted from the single-dose kinetics because of enhanced binding of the progestagens following the induction of sex hormone binding globulin (SHBG) by ethinyloestradiol. Concentrations are in the range of 1.6 to 15.2 nglml for norethisterone and 0.8 to 4.5 nglml for levonorgestrel.All the contraceptive steroids are bound to proteins in plasma. Ethinyloestradiol is 97 to 98% bound to plasma albumin. The progestagens are bound both to albumin (levonorgestrel 93 to 95%; norethisterone 79 to 80%) and more specifically to SHBG. The binding capacity of SHBG can be enhanced by treatment with ethinyloestradiol or with more conventional enzyme-inducing drugs such as phenobarbitone, carbamazepine or rifampicin.Norethisterone and levonorgestrel are chiefly metabolised by reduction in the A ring and this is followed by conjugation with glucuronide or sulphate. The metabolism of levonorgestrel is stereoselective. Ethinyloestradiol is primarily hydroxylated at the 2 position but a wide variety of hydroxylated and methylated metabolites are formed and these are present both free and as glucuronide and sulphate conjugates. Ethinyloestradiol is conjugated directly at the 3 position (unlike the progestagens) and thus is liable to enterohepatic recirculation. Ethinyloestradiol sulphate concentrations in plasma are many times higher than that of the unchanged drug.

Norgestrel and gestodene stimulate breast cancer cell growth through an oestrogen receptor mediated mechanism

“…Such concentrations are similar to plasma progestin concentrations seen in women who use oral contraceptives (Orme et al, 1983;Goldzieher, 1989). Plasma progestin concentrations seen in NORPLANT® users (0.5 nl ml-' or approximately 10-10 M) are low enough to provide no growth stimulus above control in our model system (Croxatto et al, 1988;Shoupe & Mishell, 1989, Shoupe et al, 1991.…”

Early oral contraceptive use and breast cancer: Results of another case-control study

“…However, the possibility of a different effect of the two synthetic oestrogens has little basis in either theory or in empirical observation. Mestranol is demethylated to E-O (Bolt et al, 1974) which could give rise to lower peak plasma concentrations of active oestrogen in women taking ME containing pills than in those taking E-O containing pills (Orme et al, 1983). Conceivably this could explain their lesser effect on breast cancer risk.…”

Influence of sex and oral contraceptive steroids on paracetamol metabolism.

“…While the fractional excretion of the sulphate conjugate was lower in OCS users compared to the other groups, clearance to this metabolite was not altered. The latter result is not surprising since sulphotransferase appears to be a non-inducible enzyme and, even though ethinyloestradiol is extensively sulphated (Orme, 1982), the low dose of oestrogen in the OCS would not be expected to result in significant competitive inhibition of paracetamol sulphation. It might be speculated, however, that co-administration of paracetamol and OCS would reduce the first-pass metabolism of ethinyloestradiol thereby increasing its bioavailability.…”