A number of oral contraceptive steroids undergo first-pass metabolism in the gastrointestinal mucosa. Ethinyl estradiol (mean systemic bioavailability 40% to 50%) is extensively metabolized, principally to a sulfate conjugate. In vivo studies that use portal vein catheterization and the administration of radiolabeled ethinyl estradiol have shown that the fraction of steroid metabolized in the gut wall is 0.44. In vitro studies with jejunal biopsy samples or larger pieces of jejunum or terminal ileum mounted in Ussing chambers have indicated that more than 30% of added ethinyl estradiol is sulfated. The progestogen desogestrel is a prodrug that is converted to the active metabolite 3-ketodesogestrel. Substantial first-pass metabolism of desogestrel occurs in the gut mucosa, with evidence from Ussing chamber studies for the formation of the active metabolite. Another progestogen, norgestimate, is also metabolized by the gut wall in vitro of which the principal metabolite is the deacetylated product, norgestrel oxime. It seems very likely that this will also occur in vivo. Drug interactions occurring in the gut wall have been reported with ascorbic acid (vitamin C) and paracetamol.

Oral contraceptive steroids may undergo enterohepatic circulation, but it is relevant for only estrogens, because these compounds can be directly conjugated in the liver. Animal studies show convincing evidence of the importance of the enterohepatic circulation, but studies in humans are much less convincing. The importance of the route and the rate of metabolism of ethinyl estradiol are reviewed. Some antibiotics have been reported anecdotally to reduce the efficacy of oral contraceptive steroids, but controlled stuides have not confirmed this observation. Although gut flora are altered by oral antibotics, the blood levels of ethinyl estradiol are not reduced, and one antibiotic at least (cotrimoxazole) enhances the activity of ethinyl estradiol.

The pharmacokinetics of low dose pethidine (450 micrograms kg-1) after oral administration were determined in 9 Caucasian, 9 Chinese and 9 Indian healthy volunteers under conditions of acidic urinary pH. Plasma and urine concentrations of pethidine and norpethidine were determined simultaneously by gas liquid chromatography. In all three ethnic groups the oral absorption of pethidine was rapid. The Tmax was faster in the Caucasian group (0.75 h) compared with the Chinese group (1.0 h) and the Indian group (1.5 h). No significant difference was observed in their respective lag time while the absorption t1/2 was significantly shortest in the Caucasian group who also had the highest Cmax (95.5 +/- 7.8 ng ml-1) compared with the Chinese (85.9 +/- 11.0 ng ml-1) and the Indian (58.2 +/- 3.0 ng ml-1) groups. Moderate exercise and upright posture of the Asian students might interfere with absorption and distribution of pethidine, due possibly to change in blood flow during the early stage of the study while the Caucasian subjects were in supine position. No significant difference was observed in the elimination t1/2 of pethidine between the Caucasian (8.3 +/- 0.2 h) and the Chinese (8.2 +/- 0.2 h) groups, although the Indian subjects significantly had the longest elimination t1/2 (0.1 +/- 0.3 h); this could possibly be due to their significantly higher apparent volume distribution. Under acidic urinary conditions both Chinese and Indian subjects excreted significantly more norpethidine in the urine while no difference was observed in the recovery of unchanged pethidine; this may suggest an interethnic difference in the oxidative demethylation of pethidine.

1. The intestinal mucosal metabolism of the progestogen oral contraceptive desogestrel (Dg) has been studied in vitro using the Ussing chamber technique. Histologically normal ileum or colon was obtained from eight patients undergoing various resections. The mucosal sheets were mounted between two perspex chambers. 2. Two hours after addition of [3H]-Dg (0.2 microCi; 100 ng) to the mucosal chamber, more than 90% of the steroid was present in that chamber. In studies with colon, metabolite analysis showed that 55.4 +/- 11.7% (mean +/- s.d.; n = 6) of drug present was Dg, 28.9 +/- 11.4% as unconjugated Phase I metabolites, 13.3 +/- 2.6% as sulphate conjugates and 2.5 +/- 1.5% as glucuronide conjugates. 3. By co-chromatography with authentic metabolites and mass spectrometry, it was shown that 3-keto desogestrel is formed in the mucosa. This is the active metabolite of desogestrel. A large peak of radioactivity did not co-chromatograph with any known metabolites and has been tentatively identified as ring hydroxylated products of 3-keto desogestrel. 4. The effect of the synthetic oestrogen ethinyloestradiol (EE2) on the metabolite profile of Dg was studied. In the presence of increasing concentrations of EE2 (100 ng, 1 and 10 micrograms), there was competition for sulphation such that the sulphate fraction decreased by 32, 49 and 48% respectively. 5. The results of this study indicate substantial first pass metabolism of desogestrel by the gut mucosa with evidence for the formation of the active metabolite. The extent of phase I metabolism is unusual.

1. We have searched the adverse reactions register for the years 1968‐ 84 in an attempt to evaluate data relating to reported pregnancies in women on oral contraceptive steroids (OCS) who concurrently received either an antiepileptic drug or an antibiotic. 2. A total of 43 pregnancies were reported in women on OC therapy who concurrently received antiepileptic drugs and 63 pregnancies in women receiving antibiotics. In addition the number of prescriptions for both antiepileptics and antibiotics in England are reported for the years 1973‐84.

14C-Labelled amodiaquine ([14C]AQ) has been administered to male Wistar rats by oral and intravenous routes (n = 6 for each route of administration). Excretion of total 14C-activity was predominantly in the faeces after both oral and intravenous administration. After oral administration 86 +/- 8.3% (mean +/- s.d.) of the 14C administered had been excreted (77 +/- 9% in the faeces, 7 +/- 1% in the urine and 2 +/- 2% in cage washings) over 72 h. Of the 14C administered, 4 +/- 1% was recovered from the tissues, and this was widely distributed, with the main organs of accumulation being kidney, liver, red bone marrow and spleen. After intravenous administration, 102.6 +/- 9.7% of the 14C had been excreted (90.9 +/- 9.6% in faeces, 10.9 +/- 0.8% in urine and 0.5 +/- 0.2% in cage washings) over 72 h. High-performance liquid chromatographic analysis of urine and faeces samples following oral administration of 14C-AQ (8.6 mg kg-1; base) revealed recoveries of 210 +/- 70 micrograms amodiaquine (AQ) and 123 +/- 32 micrograms desethylamodiaquine (AQm) in the faeces, and 2.4 +/- 0.5 micrograms AQ and 18.5 +/- 4.1 micrograms AQm in the urine. Female Wistar rats (n = 6) each received [14C]AQ orally and were killed at the following times: 0.5, 1, 3, 6, 24 and 48 h. Autoradiographs were prepared from each animal and these revealed significant amounts of radioactivity in the tissues at 48 h. This was accumulated maximally by liver and kidney. Radioactivity was detected in bone marrow at 48 h.(ABSTRACT TRUNCATED AT 250 WORDS)

The plasma concentrations of 3-keto-desogestrel have been measured by radioimmunoassay in a crossover study in nine healthy feamle volunteers given oral desogestrel (150 μg) and ethinyloestradiol (30 μg) and intravenous (i.v.) 3-keto-desogestrel (150 μg) and ethinyloestradiol (30 μg).

The metabolism of 17 alpha-ethinyloestradiol (EE2) to catechol and reactive metabolites by human liver microsomes was investigated. 2-Hydroxyethinyloestradiol (2-OHEE2) was either the sole or principal metabolite. Small amounts of 6-hydroxyethinyloestradiol and 16-hydroxyethinyloestradiol were produced by some of the livers. EE2 (10 microM) underwent substantial (5-20% of incubated drug), though highly variable, NADPH-dependent metabolism to material irreversibly bound to microsomal protein. 2-OHEE2 appeared to be the pro-reactive metabolite. The maximum EE2 2-hydroxylase activity was 0.67 nmol min-1 mg-1 microsomal protein, with a Km value of 8.6 microM. Oestradiol, which is mainly hydroxylated to 2-hydroxyoestradiol, was the most potent inhibitor of hydroxylase activity and exhibited competitive inhibition. Progesterone, which undergoes 2-hydroxylation to a minor extent was also a competitive inhibitor, whereas cholesterol and cortisol did not have any appreciable inhibitory effect. Primaquine was the most potent non-steroidal inhibitor but was non-competitive. Other non-steroidal compounds investigated, e.g. antipyrine, did not show any significant effect on EE2 2-hydroxylation. The results of this study suggest that EE2 2-hydroxylation is metabolised by a form(s) of cytochrome P-450 which has affinity for endogenous steroids.

The disposition of (+) and (-) primaquine (PQ) was studied in the isolated perfused rat liver (IPRL) preparation following a bolus dose (2.0 mg diphosphate salt; N = 6) of each enantiomer. Perfusate plasma concentrations of PQ and the carboxylic acid metabolite (PQm) were determined using previously reported methods. To enable the simultaneous measurement of PQ and PQm in bile a selective and reproducible HPLC assay was developed. Clearance of (-)PQ (8.8 +/- 2.9 ml min-1) was significantly greater than that of (+)PQ (5.5 +/- 1.5 ml min-1) and the apparent volumes of distribution of (-)PQ (606 +/- 182 ml) and (+)PQ (930 +/- 171 ml) were significantly different. Stereoselectivity in the hepatic elimination efficiency was manifest as a significant reduction in half-life (-)PQ 54 +/- 29 min; (+)PQ 123 +/- 33 min) and smaller area under the curve to infinity (-)PQ 254 +/- 96 micrograms ml-1.min, (+)PQ 387 +/- 108 micrograms ml-1.min) for (-)PQ when compared with (+)PQ. A significantly greater peak concentration of PQm was achieved following administration of (-)PQ (0.61 +/- 0.26 micrograms ml-1.min) than (+)PQ (0.19 +/- 0.09 micrograms ml-1). There was no difference between the sum of the areas under the curve to 4 hr for (+) and (-)PQ and the corresponding carboxylic acid metabolite (322 +/- 64 micrograms ml-1 and 317 +/- 75 micrograms ml min-1 respectively). There was no difference in the biliary clearance of (+) and (-)PQ (0.08 +/- 0.02 ml min-1 and 0.14 +/- 0.10 ml min-1 respectively) or the corresponding carboxylic acid metabolites (0.24 +/- 0.13 ml min-1 and 0.29 +/- 0.09 ml min-1). These results strongly suggest stereoselective formation of the carboxylic acid metabolite of primaquine. The significant increase in the volume of distribution of (+)PQ suggests the enantiomer has either an increased affinity for binding sites within the liver and/or erythrocytes or a decreased affinity for circulating perfusate albumin.

The bioavailability of ethinyloestradiol and levonorgestrel has been studied in 5 young women with an ileostoray following surgery for ulcerative colitis and compared to that in 5 control subjects. Single i.v. and oral doses of both drugs were administered and the bioavailability calculated from the ratio of the two areas under the plasma concentration versus time curve for the two drugs. The mean bioavailability of ethinyloestradiol in the patients with an ileostomy was 55.4 ± 10.9% (± S.D.) compared to a control value of 45.0 ± 6.1% (p > 0.1). The mean bioavailability of levonorgestrel in the ileostomy patients was 85.2 ± 13.1% compared to 104.6 ± 22.3% in the controls (p 0.1). Women who have an ileostomy following lower bowel surgery can rely on their oral contraceptive preparations being absorbed in the normal way.

The effects of a single dose of two antimalarial drugs chloroquine (CQ) and primaquine (PQ) on the pharmacokinetics of a combined oral contraceptive (O.C.) have been studied in volunteers. Each woman was studied on 3 separate occasions over 3 cycles and plasma concentrations of ethinyloestradiol (EE2) and levonorgestrel were measured by radioimmunoassay following administration of a single dose of O.C. (30 μg EE2 + 150 μg levonorgestrel) in the absence and presence of the antimalarial drugs (PQ, 45 mg; CQ, 300 mg). Neither CQ or PQ given 1 h before the O.C. had any significant effect on plasma concentrations of EE2 or levonorgestrel or on any pharmacokinetic parameter determined. There is therefore, no evidence that CQ or PQ interfere with the hepatic handling of O.C.'s. This is in contrast to previously reported inhibitory effects of PQ on the metabolism of antipyrine.

Eleven patients with severe, treatment-resistant essential or renovascular hypertension were treated with captopril after withdrawal of various multiple drug regimes. If supine diastolic blood pressure remained greater than 90 mm Hg on a maximum daily dose of 450 mg captopril, a diuretic and then a beta-adrenoceptor blocker were added. Patient-volunteered complaints were carefully noted. Mean (+/- SE) systolic and diastolic blood pressures fell from 225 +/- 6.8/131 +/- 4.4 mm Hg on various multiple drug regimes to 182 +/- 9.0/105 +/- 5.0 mm Hg on a regime including captopril. The reported and observed incidence of adverse effects were as follows: maculopapular rash (one patient); urticaria and pruritus (three patients); loss of taste (one patient); tachycardia (four patients); increased frequency of trivial infections (three patients); severe myalgia (one patient); and deterioration in renal function (one patient). However, these patients were able to continue captopril after either temporary withdrawal or dose reduction. Captopril was discontinued permanently in five patients, in two because of poor blood pressure control, in one who developed persistent severe urticaria, and in one because of marked proteinuria. In the fifth patient intractable diarrhoea occurred. Captopril lowers blood pressure very effectively in patients with severe hypertension refractory to other agents. Adverse effects are common but acceptable in this situation where prognosis is poor if blood pressure is not adequately controlled.