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Biliary excretion and hepatotoxicity of contraceptive steroids
Abstract
The naturally occurring oestrogens and certain synthetic sex hormones, particularly those with a 17α-alkyl function, can interfere with hepatic excretory function by impairment of biliary excretion. This may be manifest in abnormal liver function tests or it may appear as cholestatic jaundice.
The naturally occurring and synthetic sex hormones undergo extensive biliary excretion and enterohepatic circulation but the extent to which this occurs varies with species and structure. They appear in bile in the form of conjugates and metabolic conjugation is crucial for their biliary excretion. Impairment of metabolic conjugation, for genetic reasons, or because the presence of an inhibitor may lead to defective biliary excretion of steroids.
The natural oestrogens and contraceptive steroids tend to undergo extensive enterohepatic circulation which causes them to persist in the body. This factor has an important bearing on their pharmacokinetics and this has not been adequately considered.
The hepatic dysfunction induced by natural and synthetic sex hormones may affect the capacity of the liver to excrete other compounds of endogenous (e. g. bilirubin) and exogenous (e. g. other drugs) origin.
The mechanism(s) whereby natural and synthetic sex hormones impair hepatic excretion is not known. These compounds can influence various factors involved in biliary excretion such as metabolic conjugation, hepatic uptake and secretion and permeability of the biliary tree. Steroid induced changes in bile composition may be important in both cholestasis and in the formation of lithogenic bile.
... The Committee on Safety of Medicines (CSM) has details of at least 38 women who, while taking oral contraceptives, have become pregnant when given one of a variety of antibiotics (listed inTable 7). Synthetic oestrogens and progestogens are extensively excreted in the bile of both humans and animals, principally as glucuronide or sulphate conjugates (Fotherby, 1974; Smith, 1974). These conjugates, after reaching the gut are hydrolysed by enzymes present in the gut bacteria to liberate the unchanged steroid which can then be reabsorbed. ...
... These conjugates, after reaching the gut are hydrolysed by enzymes present in the gut bacteria to liberate the unchanged steroid which can then be reabsorbed. This is the basis of the enterohepatic circulation (Hanasono & Fischer, 1974; Smith, 1974) although only ethinyloestradiol undergoes an enterohepatic circulation as the unchanged and pharmacologically active drug. Norethisterone and levonorgestrel undergo enterohepatic circulation only as the reduced metabolites which have little or no pharmacological activity. ...
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This document attempts to fill in some gaps with regard to the clinical pharmacology of oral contraceptives (OCs). The total dose level cannot be reduced much further without impairing the contraceptive efficacy of the drug. Plasma concentration of steroids varies widely from individual to individual. The bioavailability of norethisterone and ethinyl estradiol (EE) is incomplete when drugs are given orally as opposed to intravenously. Reduced norethisterone bioavailability is due to a 1st pass effect; drugs may undergo 1st pass elimination either in the gut wall or in the liver. With EE, the values of EE sulphate were higher when EE was administered orally than when it was given intravenously. This suggests that after oral dosing, a significant part of the 1st pass effect is due to sulphate conjugation in the gut wall. Norethisterone and levonorgestrel are extensively bound to albumin and sex hormone binding globulin in plasma. This binding capacity can be enhanced by EE and drugs such as phenobarbitone. EE is also bound to albumin. While OC therapy may interfere with the activity of the other drug treatment given at the same time, this is not clinically of major importance. OCs may diminish the effects of anticoagulants, of oral hypoglycemic drugs, or of antihypertensive drugs. Likewise, the effect of OCs may be altered by the simultaneous administration of other drugs. It is also apparent that the effect of OCs may be enhanced by vitamin C. Rifampicin, a potent inducer of hepatic microsomal drug metabolizing enzymes, does diminish the efficacy of OCs. Anticonvulsants and antibiotics are also in the same category. The interaction between OCs and antibiotics is probably the most controversial of all. There have been reports in the literature about women who have become pregnant while taking OCs and antibiotics. It is likely that the majority of women are not at risk of contraceptive failure when using a broad spectrum antibiotic at the same time as the OC.
... Synthetic oestrogens and pTOgestogens are extensively excreted in bile, mainly as glucuronide conjugates (Fotherby, 1974). Subsequently they undergo enterohepatic circulation (Smith, 1974) since gut microfiora possess a powerful hydrolytic enzyme, P-glucuronidase, (Hawksworth, Drasar & Hill, 1971) which splits the conjugate, liberating intact drug which can then be reabsorbed. Treatment with oral antibiotics may be expected to interfere with this hydrolytic process and hence to reduce or eliminate any steroid reabsorption from the gastrointestinal tract. ...
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Since 1971 there have been reports of pregnancies and breakthrough bleeding in women using oral contraceptives (OCs) and some antibiotics. Rifampicin appears to induce enzymes that increase the metabolism of estrogens and progesterone in OCs. However, ampicillin, chloramphenicol, and sulphamethoxypyridazine may impair the action of OCs in a potentially more hazardous manner. Synthetic estrogens and progestogens are extensively excreted in bile as glucuronide conjugates. Ordinarily, gut microflora produce a hydrolytic enzyme that splits the conjugates, allowing reabsorption of the steroids from the gastrointestinal tract. Ampicillin and other antibiotics interfere with the hydrolytic process by reducing the population of microflora that produce the enzyme (beta-glucuronidase). In experiments in which rats were given labeled steroids, ampicillin and neomycin reduced biliary excretion of steroids by 70%, and the reduction in biliary excretion correlated well with the reduction in bacterial population. More information on the incidence of antibiotic-OC interactions in practice, controlled studies of changes in plasma levels of steroids produced by common antibiotics, and ways to identify women who are at particular risk of being affected by antibiotics are needed.
... Norethisterone and ethinyloestradiol are the synthetic steroids present in many combination type oral contraceptive preparations. Animal studies have established that both steroids undergo extensive biliary excretion, principally as glucuronides, and enterohepatic circulation (Steinetz, Meli, Giannina & Beach, 1967;Hanasono & Fischer, 1974;Smith, 1974). Neomycin has previously been reported to interfere with the enterohepatic circulation of radioactivity associated with the synthetic oestrogen mestranol, by affecting the viability of the gut microflora which are partly responsible for deconjugation (Brewster, Jones & Symons, 1977). ...
This study reports values of serum lipids, lipoproteins, and the relative fatty acid composition of lecithin and cholesterol ester in 20 women with typical polycystic ovary syndrome (PCO). These values were compared with values of 22 regularly menstruating women without clinical evidence of androgen excess. Higher levels of triglycerides in serum ( P P P No correlations between lipids and sex hormones were found. Body weights and blood pressures were higher in the PCO group. The results indicate that PCO women could be at increased risk for coronary heart disease, because an increased serum triglyceride level, body weight, and blood pressure are considered to be risk factors of coronary heart disease.
Although there is remarkably little known about the effect of pregnancy on the human liver and particularly about its effect on the secretion and composition of bile there is evidence, much of it indirect and some of it controversial, that there is a general alteration in liver function during pregnancy (11,13,27,33,38,68, 69,71). In the latter part of pregnancy one finds an increased activity of serum alkaline phosphatase and leucine amino peptidase which is not entirely attributable to placental contributions. There is an increased activity of 5′-nucleotidase and there is a general hyperlipemia (7,8,11,14,62,70). This latter phenomenon, first documented by Virchow in 1867, must involve the liver which plays such a central role in lipid metabolism. And it must involve several different mechanisms. Although the concentrations of total triglycerides, cholesterol, phospholipids and free fatty acids are all increased the relative increase of triglyceride is greater than that of cholesterol which is in turn greater than that of phospholipid. In fact plasma lysolecithin is selectively decreased and quite dramatically (70,76).
Most foreign compounds (xenobiotics) are metabolised in vivo producing conjugates (e.g. glucuronldes, sulphates, amino acid conjugates), which are fairly strong organic acids and are readily excreted in either the urine or bile (see Williams and Millburn, 1975). Compounds excreted in the bile may eventually be eliminated in the faeces but prior to this they can undergo an enterohepatic circulation or be metabolised in the intestine by the enzymes of the gut microflora. The latter can carry out a considerable number of reactions on xenobiotics, particularly hydrolytic and reductive reactions, and in certain instances this can lead to the production of toxic metabolites (see Williams 1972). If the excretion of a compound in the bile leads to an enterohepatic circulation this will prolong the presence of the compound or its metabolites in the body. This increases the chances of toxic reactions occurring and may prolong the pharmacological effects of some substances. It is, therefore, important to know the types of xenobiotic compounds excreted in bile and whether this excretory pattern varies with species.
During administration of an oral contraceptive pill containing 0.150 mg desogestrel and 0.030 mg ethinyles-tradiol, routine liver function tests were performed before and after 3, 6, and 12 months of treatment. No significant changes in serum amino aspartate transferase or serum alanine amino transferase were recorded during treatment. The serum alkaline phosphatase level decreased significantly after 3 and 6 months and then returned to normal. No changes in serum bilirubin were found. Briefly, no significant changes in the liver function tests were found, indicating no impairment of the liver function throughout the medication period.
87.9% of a given dose of [3H]Norethisterone ([3H]N) and 76.7% of [3H]Ethinyloestradiol ([3H]EE2) were excreted in the bile of male heterozygous Gunn rats in 2 hours Similarly, 86.9% of a given dose [3H]N and 84.0% of [3H]EE2 were excreted in the bile of male homozygous Gunn rats in 2 hours. In both heterozygous and homozygous rats glucuronide conjugates were present. Despite the lesion in UDP-glucuronyltransferase, the homozygous rats is able to conjugate the synthetic steroids apparently normally.
Hormones, particularly those produced by the gonads, and their synthetic analogs have been the subject of controversy concerning their roles in the process of carcinogenesis. Experimental evidence, dating from 1916 [118] (Table 1), that estrogens can be potent carcinogens was overlooked or lightly dismissed by many because of a prevalent belief that the body should be able to metabolize these physiologic compounds without toxic effects. The relevance of animal experiments to the human cancer problem was also questioned. During the past four decades, a variety of naturally occurring and synthetic estrogens, progestins, and androgens have been manufactured and prescribed in ever-increasing amounts for replacement, treatment of cancer, prevention of abortion, suppression of lactation, contraception, and other purposes without adequate attention to their carcinogenic potential.
A short review on steroid absorption and enterohepatic recycling in man with special emphasis on contraceptive and related steroids is presented. Some new experimental data on the intestinal metabolism of steroids is described and includes further observations on the effect of antimicrobial agents on steroid hormone metabolism. Evidence is presented that plasma levels of steroids may be influenced if the intestinal microflora is altered. Some formation of biologically active steroids, like estradiol, may occur in the intestinal tract and this may have both biological and pathological consequences and may be influenced by such factors as diet and sex. It is concluded that our knowledge of the intestinal and especially, the mucosal metabolism of steroids is scanty and further studies are needed to clarify the role of the intestine and enterohepatic circulation in determining the bioavailability of natural and synthetic steroids.
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The present knowledge on absorption and enterohepatic recycling of contraceptive steroids in human subjects is outlined and some recent results obtained are discussed in this review. The new experimental data relate to the effects of antimicrobial agents on steroid hormone metabolism The plasma levels of steroids may be influenced if the intestinal microflora are altered (as in antibiotic therapy). Some formation of biologically active steroids, such as estradiol, may occur in the intestinal tract and this may be consequential both biologically and pathologically, influenced by factors such as diet and sex. Knowlege of bioavailability of natural and synthetic hormones in terms of their metabolism in the intestine and enterohepatic circulation is scanty. Further studies are called for.
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There is increasing evidence from various types of studies that commonly prescribed drugs can interact with OCs (oral contraceptives), leading to a decreased contraceptive efficacy. Additionally, contraceptive steroids influence the response to the other drug therapies as well. Antituberculous drugs enhance metabolism of the estrogenic component of OCs, thus reducing the contraceptive effect. Other types of drugs which have been shown to interfere with the contraceptive effect of OCs are: anticonvulsant, antibiotic, and analgesic drugs. The effect of OCs on anticoagulant, antihypertensive, antidiabetic, and antidepressant drugs is also outlined. Tables and graphs illustrate some of these disadvantegeous drug interactions.
The sera of rats treated with alpha-naphthylisothiocyanate, an agent reported to cause intrahepatic cholestasis, and of rats treated with carbon tetrachloride, are examined for evidence of leakage of bile into blood. The levels of the four bile components assayed, namely IgA, free IgA secretory component, the biliary isoenzyme of 5'-nucleotidase and of direct reacting (conjugated) bilirubin, were all elevated in the sera of rats treated with alpha-naphthylisothiocyanate. No change in any of these components was found in rats treated with carbon tetrachloride, indicating that their appearance in serum is not an inevitable consequence of damage to hepatocytes. As the bile components assayed reach bile by three different routes. their rapid appearance in the sera of rats treated with alpha-naphthylisothiocyanate indicates reflux of bile into blood, presumably as a result of mechanical obstruction of intraheptic bile ducts.
We believe that the probable "estrogen-free" site which is present in the liver while a patient is on estrogens gives a conductive environment for local growth of prostate malignancy. We report 1 patient who improved with local irradiation and 2 others who stabilized and symptomatically improved with chemotherapy. Hopefully, future reports will shed more light on the treatment of hepatic metastases from prostatic adenocarcinoma.
Seventy-one percent of a given dose of [3H]-ethinylestradiol ([3H]-EE2) and 76.0% of a given dose of [3H]-norethisterone ([3H]-N) were excreted in the bile of female rats in 4 h. The majority of radio-activity appeared in the glucuronide fraction. Characterization of the hydrolysed glucuronide fraction obtained after administration of [3H]-EE2 gave evidence that approximately 10.0% of the administered dose may be directly conjugated to form ethinylestradiol glucuronide. In contrast, there was no evidence of direct conjugation of norethisterone.In a linked rat preparation 15.4% of the given dose of [3H]-EE2 was excreted in the bile of control recipient rats in 7 h; this was reduced to 5.2% in neomycin pretreated and 6.0% in ampicillin pretreated animals. With [3H]-N, 13.2% of the dose was excreted in the bile of control recipient rats in 7 hours and this was reduced to 3.6% in neomycin pretreated and 3.9% in ampicillin pretreated animals.These results show that antibiotic treatment reduces the enterohepatic circulation of synthetic steroids in the rat.
Liver function tests were performed in 80 women who were taking depomedroxyprogesterone acetate (DMPA) and norethisterone oenanthate (NET-OEN) as contraceptives for different durations. No significant change was found in the thymol turbidity, zinc turbidity, serum alkaline phosphatase, serum bilirubin, serum glutamic oxalacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT). However, there were a significant decrease in the prothrombin activity and a significant impairment in the clearance of bromsulphthalein (BSP) in all the groups studied.
Summary The elimination of practolol in bile was studied in six patients who received a single oral dose of 400 mg within six days
of undergoing biliary surgery. Bile collections were made from a T-tube drain left in the common bile duct after removal of
multiple biliary calculi. There was wide variation in the concentration of practolol in bile and in the total amount of practolol
excreted in bile during the 48 hour period after dosage. Two patients excreted 23 per cent and 41 per cent of the 400 mg dose
in bile, whereas the excretion in the other four patients was only one per cent to four per cent of the oral dose. The mean
urinary excretion of practolol in 48 hours was 74.2±S.E. 8.4 per cent of the ingested dose, and the total elimination (biliary
plus urinary) was 86.5±S.E. 7.6 per cent. The total elimination ranged from 92 per cent to 105 per cent in four of the patients.
The mean elimination half-life of practolol in blood was 6.4±S.E. 0.5 hours. This was significantly less than the half-life
in normal subjects receiving the same practolol dose. Since complete or near-complete urinary excretion of practolol is found
in normal subjects, the presence of large amounts of drug in the bile suggests that enterohepatic recirculation of the drug
occurred in some of the patients at least. This is a possible explanation of the shortened half-life in these patients in
whom drug was being removed with bile. The four patients with low excretion of practolol in bile were receiving other drugs
at the time of the study. These included nitrazepam, diazepam and tetracycline which are known to have substantial biliary
elimination either in animals or man. It is suggested that competition for biliary excretion may have occurred and this may
represent a drug interaction of possible clinical significance.
Women using combined-type oral contraceptives show a progressive increase in serum activity of lysosomal enzymes (beta-glucuronidase and beta-acetyl-glucuronidase) during the first 6 cycles of treatment; thereafter, the enzyme activities remain relatively constant. The increase in enzyme activity appears to be approximately proportional to the total steroid intake per cycle and not to any particular steroid or combination of steroids. These findings suggest that oral contraceptives of choice should contain the minimum amount of steroids compatible with high efficacy and patient acceptability.
Twenty-one women were treated with high doses of depot-medroxyprogesterone acetate (1000 mg/week im) for 6 months as part of the treatment of endometrial carcinoma. The relative fatty acid composition of serum lecithin and cholesterol ester were analyzed. In previous studies low doses of medroxyprogesterone acetate (MPA), in contrast to progestins of the 19-nor-testosterone series, have been shown not to affect the fatty acid composition of serum lecithin and cholesterol ester. However, the high doses of MPA used in this study increased linoleic acid and decreased arachidonic and di-homogammalinolenic acids in serum lecithin. The ability of a steroid to induce this shift has been ascribed to its androgenicity. MPA is considered to have weak, if any, such properties. The findings of this study emphasize the necessity to delineate effects on metabolism of different doses and administrative routes of any particular steroid.
The pharmacokinetics of the commonly used contraceptive steroids ethinyloestradiol and levonorgestrel were investigated after oral and intravenous administration in six women with cystic fibrosis. The results were compared with data obtained from healthy women of similar age. The total body clearance of ethinyloestradiol was significantly higher in the patients with cystic fibrosis (0.61 (SD 0.19) l/h/kg) than in control women (0.32 (0.16) l/h/kg; p less than 0.02). In addition, the oral bioavailability of ethinyloestradiol was greater in women with cystic fibrosis than in controls (76.9% (11.7%) compared with 47.3% (7.5%); p less than 0.001). As a result of these two changes, the area under the plasma concentration--time curve after an oral dose of ethinyloestradiol was similar in patients and controls. The pharmacokinetics of levonorgestrel did not differ significantly between patients with cystic fibrosis and healthy women. The data suggest that women with cystic fibrosis will receive similar contraceptive protection from these steroids as do healthy women.
The relative fatty acid compositions of serum lecithin and cholesterol ester were studied during continuous treatment with an estrogen/progestogen combination. All 26 women who participated suffered from climacteric complaints and were given one tablet daily containing 2 mg of 17 beta-estradiol, 1 mg of estriol, and 1 mg of norethindrone acetate. Blood samples were taken before treatment and after 3 and 12 months of treatment. In serum lecithin, a decrease (p less than 0.01) in stearic acid concomitant with an increase of linoleic (p less than 0.05) and arachidonic (p less than 0.01) acids was recorded. The most evident changes noted in cholesterol ester were decreased levels of stearic (p less than 0.01), oleic (p less than 0.05), and arachidonic (p less than 0.001) acids. Polyunsaturated acids of the n-6 series are precursors for prostaglandins and leukotrienes. In the present study an increase of dihomo-gamma-linolenic, linoleic, and arachidonic acids in serum lecithin was found after treatment, and theoretically this finding may have an impact on the prostacyclin-thromboxane balance.
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 β-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 L/kg. During long term treatment with oral contraceptive steroids, steady-state plasma concentrations of ethinyloestradiol (24 hours after administration) are between 10 and 200 pg/ml. 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 ng/ml for norethisterone and 0.8 to 4.5 ng/ml 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.
The oral contraceptive steroids are involved in drug interactions of clinical significance. While the effect of contraceptive steroids on other drugs is small and unlikely to be of clinical significance, failure of contraception often occurs if enzyme-inducing agents such as rifampkin, phenobarbitone or carbamazepine are coadministered. Oral antibiotics do not seem to cause a significant loss of contraception in the large majority of women. Vitamin C will enhance the effect of contraceptive steroids by competing for sulphate conjugation in the gut wall, thus leading to increased bioavailability of ethinyloestradiol.
We have described a number of microbial transformations of the three classes of steroids occurring in the human intestine. These include: hydrolysis, dehydrogenation (hydroxyl and nuclear), dehydroxylation, epimerization, and side chain cleavage reactions all leaving the steroid nucleus intact. In many cases the responsible organism has been isolated and the enzyme(s) has been purified and studied. Areas of paucity in information are nonetheless evident. Isolation of unknown organisms, details of the mechanism of action of most of the described enzymes, and a thorough understanding of the biological significance of the reaction products to the host must await further research. New applications of these enzymes remain in the future.
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The biliary excretion and intestinal metabolism (including intestinal mucosa and small intestine and bowel) of progesterone and estrogens in humans are reviewed here along with presentation of experimental results from other mammalian systems. In general, the biliary excretion of estrogens and the enterohepatic circulation of estrogen metabolites are more extensive than for progesterone. These processes may be of greater physiological importance because of the possible reformation of biologically active estrogens in the intestine, which occurs 2 ways: 1) by hydrolysis of biliary estrogen conjugates and absorption of the unconjugated estrogens which may partly reach general circulation, and 2) by production of biologically active estrogens from neutral steroids or less active estrogens in the intestinal tract, followed by absorption. Here, the kidneys also play a significant role in estrogen metabolism and conjugation. The quantitative contribution of liver, kidneys, and intestine to estrogen metabolism cannot be accurately assessed at present, but the liver and intestines probably play the most significant role, followed by the kidneys. Progesterone (from orally administered doses) and its metabolites are extensively metabolized in the intestine to compounds with less progestational activity; hence, synthetic progestins may alter the intestinal flora which in turn may influence the plasma levels of these compounds. On these subjects more research in indicated.
Large inerindividual differences occur in the plasma concentration of contraceptive steroids. With the present tendency to decrease the dose of progestagen and oestrogen any factor which reduces the bioavailability of the lower dose preparations becomes very important. The possibility that other drugs and environmental chemicals may interact with contraceptive steroids is currently being investigated. Clinical reports suggest that the most important interacting drugs are the antituberculosis agent rifampicin, anticonvulsants and antibiotics. In the case of the first two, evidence is available suggesting that microsomal enzyme induction, either in the liver or the gut wall, is the operative mechanism. Antibiotics interfere with the pharmacokinetics of contraceptive steroids by interfering with their enterohepatic circulation in animal species; whether this is operative in man is still unclear.
Other environmental and constitutional factors such as smoking, variations in diet, and concurrent disease may alter the disposition of contraceptive steroids and affect response accordingly. Additional studies are needed to estimate the significance of such interactions.
When bile containing tritiated conjugates of norethisterone, collected from donor rats, was infused either into the duodenum or caecum of recipient rats, 23.5% and 42.4% of the dose was excreted in the bile respectively. Pretreatment of recipient rats with ampicillin or neomycin (200 mg/kg/day for 4 days) or neomycin + lincomycin (100 + 100 mg/kg/day for 4 days) significantly reduced (P < 0.001) the amount of steroid appearing in the bile of recipient rats following intracaecal administration of conjugates. There was a correlation between the reduction in enterohepatic circulation (EHC) and suppression of the gut flora. Ampicillin treatment caused a reduction in the anaerobic element and partial suppression of aerobes. Neomycin pretreatment caused a great reduction in the aerobic flora, but only a small reduction in anaerobes. Following neomycin + lincomycin treatment both the aerobic and anaerobic flora were dramatically reduced.Rifampicin treatment (200 mg/kg/day for 4 days) did not cause a reduction in the EHC of norethisterone, or in the concentration of aerobic or anaerobic flora in the caecum. However, the aerobic flora were rifampicin resistant. To investigate the onset of this resistance recipient rats were treated with rifampicin for 1, 2 or 3 days and a graded effect both on the EHC of the steroid and the incidence of resistant organisms was evident.Following ampicillin administration (4 days) both the EHC and the gut flora were normalized 14 days after the final drug treatment.
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