A study of interaction of low-dose combination oral contraceptive with ampicillin and metronidazole

Joshi, Jayashree; Joshi, Usha; Sankholi, G.M.; Krishna, U.; Mandlekar, Ajita; Chowdhury, Vishwajit S.; Hazari, K.; Gupta, Kriti; Sheth, U K; Saxena, B.N.

doi:10.1016/0010-7824(80)90089-x

Cited by 63 publications

(17 citation statements)

References 8 publications

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“…These observations confirm other information in the literature that show that ampicillin does not interfere with oral contraceptive steroid therapy in women (Friedman et al, 1980;Joshi et al, 1980). One of the problems of studying this interaction is that prolonged use of antibiotics will lead to the development of resistant organisms.…”

Section: Antibioticssupporting

confidence: 89%

The third S.K. & F. Prize lecture, University of London, December 1981. The clinical pharmacology of oral contraceptive steroids.

Orme¹

1982

Brit J Clinical Pharma

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Oral contraceptive steroids have been in regular use for some 20 years and are taken by about 50 million women worldwide. It is therefore surprising to find that information on the clinical pharmacology of such commonly used drugs is so lacking. There are a number of possible reasons for this state of affairs, but at least partly this is due to the fact that oral contraceptive steroids occupy a unique position in therapeutics in being given to a healthy group of women. In addition, oral contraceptive steroids were, for a long time, given in supratherapeutic doses. With the realisation that side effects were occurring, and that some of these were clearly dose related, the dose of steroid in the combined preparations was gradually reduced. As the dose has been reduced, the problems associated with interindividual variations in elimination have become apparent, thus highlighting our previous lack of knowledge. The first combination preparation to undergo large scale clinical trial was Enovid which contained 150 ,tg of oestrogen (mestranol) and 10 mg of progestogen (norethynodrel). Most combined preparations now contain 1 mg or less of progestogen and about 30 ,ug of the oestrogen (ethinyloestradiol). The latest triphasic preparations contain an even lower total dose of steroid.We are now at such a stage that it would be difficult to reduce the total dose level much further without impairing the contraceptive efficacy of the preparation. Any factor which interferes with the bioavailability of the contraceptive steroids is likely to cause failure of contraception and this is reflected in the increasing interest in drug interactions with the contraceptive steroids. Pharmacokinetics of contraceptive steroidsThere is a wide inter-individual range in the plasma concentrations of steroids, measured in blood samples taken 10-12 h after dosing in women on long term treatment. Figure 1 shows the plasma concentrations of ethinyloestradiol and levonorgestrel given at two dose levels to groups of women. There is a 20-30 fold variation in the steady state plasma concentration of each steroid.

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Section: Antibioticssupporting

confidence: 89%

The third S.K. & F. Prize lecture, University of London, December 1981. The clinical pharmacology of oral contraceptive steroids.

Orme¹

1982

Brit J Clinical Pharma

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“…However, in the intervening 20 years there has been no verification that the relationship was causal. Moreover, earlier studies suggested that ampicillin had no effect on oral contraceptive effec- tiveness (Friedman et al, 1980;Joshi et al, 1980). Other than the rifamycins, no antibiotics have been shown to alter the pharmacokinetics of ethinylestradiol in humans (Shenfield and Griffin, 1991).…”

Section: Downloaded Frommentioning

confidence: 99%

A Comprehensive in Vitro and in Silico Analysis of Antibiotics That Activate Pregnane X Receptor and Induce CYP3A4 in Liver and Intestine

Yasuda

Ranade²,

Venkataramanan³

et al. 2008

Drug Metab Dispos

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ABSTRACT:We have investigated several in silico and in vitro methods to improve our ability to predict potential drug interactions of antibiotics. Our focus was to identify those antibiotics that activate pregnane X receptor (PXR) and induce CYP3A4 in human hepatocytes and intestinal cells. Human PXR activation was screened using reporter assays in HepG2 cells, kinetic measurements of PXR activation were made in DPX-2 cells, and induction of CYP3A4 expression and activity was verified by quantitative polymerase chain reaction, immunoblotting, and testosterone 6␤-hydroxylation in primary human hepatocytes and LS180 cells. We found that in HepG2 cells CYP3A4 transcription was activated strongly (>10-fold) by rifampin and troleandomycin; moderately (>7-fold) by dicloxacillin, tetracycline, clindamycin, griseofulvin, and (>4-fold) erythromycin; and weakly (>2.4-fold) by nafcillin, cefaclor, sulfisoxazole, and (>2-fold) cefadroxil and penicillin V. Similar although not identical results were obtained in DPX-2 cells. CYP3A4 mRNA and protein expression were induced by these antibiotics to differing extents in both liver and intestinal cells. CYP3A4 activity was significantly increased by rifampin (9.7-fold), nafcillin and dicloxacillin (5.9-fold), and weakly induced (2-fold) by tetracycline, sufisoxazole, troleandomycin, and clindamycin. Multiple pharmacophore models and docking indicated a good fit for dicloxacillin and nafcillin in PXR. These results suggest that in vitro and in silico methods can help to prioritize and identify antibiotics that are most likely to reduce exposures of medications (such as oral contraceptive agents) which interact with enzymes and transporters regulated by PXR. In summary, nafcillin, dicloxacillin, cephradine, tetracycline, sulfixoxazole, erythromycin, clindamycin, and griseofulvin exhibit a clear propensity to induce CYP3A4 and warrant further clinical investigation.

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“…Broad spectrum antibiotics have also been implicated in causing failure of contraception in women on the pill. There are a number of case reports (Dossetor, 1975;Bacon & Shenfield, 1980;De Sano & Hurley, 1982) although clinical studies have been singularly unsuccessful in demonstrating any consistent effect of antibiotic agents on plasma concentrations of synthetic steroids (Friedman et al, 1980;Joshi et al, 1980;Back et al, 1982).…”

Section: Introductionmentioning

confidence: 99%

“…In one clinical study involving nine women on long term OCS, cotrimoxazole failed to cause any decrease in circulating plasma steroid concentrations . Despite the paucity of experimental evidence in humans that broad spectrum antibiotics alter plasma concentrations of OCS (Friedman et al, 1980;Joshi et al, 1980;Back et al, 1982) . Individuals at risk are most probably (but not exclusively) women with a low bioavailability of EE due to extensive steroid metabolism in the gut wall and liver; a large enterohepatic circulation of EE and a particularly susceptible gut microflora able to hydrolyse steroid conjugates (Back & Orme, 1984;Shenfield, 1986).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Committee on Safety of Medicines yellow card reports on oral contraceptive‐drug interactions with anticonvulsants and antibiotics.

Back

Grimmer

Orme

et al. 1988

Brit J Clinical Pharma

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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.

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A study of interaction of low-dose combination oral contraceptive with ampicillin and metronidazole

Cited by 63 publications

References 8 publications

The third S.K. & F. Prize lecture, University of London, December 1981. The clinical pharmacology of oral contraceptive steroids.

The third S.K. & F. Prize lecture, University of London, December 1981. The clinical pharmacology of oral contraceptive steroids.

A Comprehensive in Vitro and in Silico Analysis of Antibiotics That Activate Pregnane X Receptor and Induce CYP3A4 in Liver and Intestine

Evaluation of Committee on Safety of Medicines yellow card reports on oral contraceptive‐drug interactions with anticonvulsants and antibiotics.

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