The effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive

Barditch‐Crovo, Patricia; Trapnell, Carol Braun; Ette, Ene I.; Zacur, Howard A.; Coresh, Joseph; Rocco, L; Hendrix, Craig W.; Flexner, Charles

doi:10.1016/s0009-9236(99)70138-4

Cited by 101 publications

(97 citation statements)

References 31 publications

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“…The cytochrome P450 (CYP) enzyme system in the liver plays a significant role in drug metabolism, and drugs (possibly including the herbal medication, St John's Wort) that induce these enzymes can cause increased elimination of contraceptive steroids, resulting in reduced reliability and, consequently, unplanned pregnancy. 3 A variety of potent enzyme inducers known to have deleterious effects on hormonal contraceptives include some antiepileptics (carbamazepine, oxcarbazepine, phenytoin, phenobarbital, primidone, topiramate), [16][17][18][19] antibiotics (rifampicin, rifabutin), [20][21][22][23][24] antifungals (griseofulvin), 25 protease inhibitors (amprenavir, atazanavir, nelfinavir, lopinavir, saquinavir, ritonavir), 26 and non-nucleoside reverse transcriptase inhibitors (efavirenz, nevirapine). 27 There have been sporadic reports of Implanon failure due to suspected interaction with concomitantly administered drugs, resulting in intrauterine 10,11,28 or ectopic [29][30][31] pregnancies.…”

Section: Discussionmentioning

confidence: 99%

Failure of Implanon® on antituberculous therapy

Gbolade¹

2010

OAJC

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Implanon ® , a contraceptive implant, is increasingly being used because of its efficacy and nonuser-dependent nature. However, as for other steroid contraceptives, its efficacy can be reduced by enzyme-inducing drugs, such as antituberculous medication, resulting in unplanned pregnancy. We present the case of a 27-year-old para 1 + 0 referred to us for termination of a pregnancy that resulted from failure of Implanon during concomitant treatment with Rifinah ® (a rifampicin-isoniazid combination). All health care providers should be aware of the adverse effects of hepatic enzyme inducers on hormonal contraceptives, obtain details of current contraceptive methods from women of reproductive age, and refer them to contraceptive and reproductive health care professionals as appropriate for optimal management. This will ensure that such women do not experience the psychologic trauma of a termination of pregnancy.

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Section: Discussionmentioning

confidence: 99%

Failure of Implanon® on antituberculous therapy

Gbolade¹

2010

OAJC

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“…Among women taking rifampin and OCs, 75% experienced intermenstrual bleeding, and 6% became pregnant (Reimers and Jezek, 1971). The effects of rifampin on the disposition kinetics of ethinylestradiol resulting in a substantial decrease in area under the curve have been thoroughly studied (Barditch-Crovo et al, 1999). Likewise, van Dijke and Weber (1984) reported an array of case studies involving women taking concomitant griseofulvin and OCs who reported menstrual cycle disturbances and pregnancies.…”

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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“…18,19) Clinically relevant plasma concentrations of EE 2 are very low (Ͻ2 nM). 7) These values indicate that the possibility of substrate inhibition of EE 2 3-sulfation in human liver can be completely ruled out. K m values for the 2-hydroxylation and 3-glucuronidation of EE 2 in pooled liver microsomes were 3.34 and 23.3 mM, respectively, and the K m value for the 3-sulfation of EE 2 in pooled liver cytosol was 2.85 mM ( Table 1).…”

Section: Discussionmentioning

confidence: 93%

“…Plasma concentrations of EE 2 achieved during normal therapy are very low (Ͻ2 nM). 7) However, most previous in vitro studies used substantially high EE 2 substrate concentrations (Ͼ10 mM). A recent study using human hepatocytes in vitro at a substrate concentration of 1 nM demonstrated that the major EE 2 metabolites are direct conjugates, with hydroxylation representing minor pathways, and suggested that the production of EE 2 -3-sulfate was increased by pretreatment of hepatocytes with rifampicin.…”

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confidence: 99%

Interindividual Variability in 2-Hydroxylation, 3-Sulfation, and 3-Glucuronidation of Ethynylestradiol in Human Liver

Shiraga

Niwa

Ohno

et al. 2004

Biological & Pharmaceutical Bulletin

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Ethynylestradiol (EE 2 ) is commonly used as the major estrogenic component in many oral contraceptive formulations. Orme et al. 1) reported that EE 2 is metabolized by multiple pathways, and there is a large interindividual variability in the routes and rates of metabolism of EE 2 in humans. In addition, marked interindividual differences in the pharmacokinetic parameters of EE 2 have been reported.1) The reported systemic bioavailability of orally ingested EE 2 ranges from 20 to 65%. 1) Factors that could affect oral clearance of a drug include absorption from the gastrointestinal tract, protein binding, intrinsic hepatic clearance, hepatic blood flow, and renal clearance. Urinary excretion of unchanged EE 2 was very low, 2) suggesting that EE 2 is mainly eliminated by metabolism. The 2-hydroxylation of EE 2 is mainly catalyzed by CYP3A, CYP2C, and CYP2E enzymes, 3,4) and this route is one of the main metabolic pathways in humans.5,6) Additionally, sulfation and glucuronidation also play important roles in the metabolism of EE 2 . EE 2 -3-glucuronide and EE 2 -3-sulfate are eliminated into the gastrointestinal tract, hydrolyzed by gut bacteria to EE 2 , and subsequently reabsorbed. Rifampicin, an inducer of CYP3A, has been reported to significantly increase the oral clearance of EE 2 .7) This interaction is thought to reflect the significant contribution of CYP3A enzymes to the metabolism of EE 2 . It is well known that there are large interindividual differences in the expression levels and catalytic activities of CYP3A enzymes in human liver. 8)Patki et al. 9) indicated that the intrinsic clearance of triazolam, a CYP3A substrate, and CYP3A protein in human liver are reduced in the elderly.In vitro studies are useful for clarifying the role of respective enzymes on the systemic drug clearance. Plasma concentrations of EE 2 achieved during normal therapy are very low (Ͻ2 nM).7) However, most previous in vitro studies used substantially high EE 2 substrate concentrations (Ͼ10 mM). A recent study using human hepatocytes in vitro at a substrate concentration of 1 nM demonstrated that the major EE 2 metabolites are direct conjugates, with hydroxylation representing minor pathways, and suggested that the production of EE 2 -3-sulfate was increased by pretreatment of hepatocytes with rifampicin.10) The initial rate of conjugate formation was reported to be EE 2 -3-sulfateϾEE 2 -3-glucuronide in human hepatocytes. 10) In the current study, we investigated interindividual variability of the 2-hydroxylation, 3-glucuronidation, and 3-sulfation of EE 2 using human liver microsomes and cytosol in the presence of the respective cofactors. Additionally, interindividual variability of the relative contribution of CYP3A to the 2-hydroxylation of EE 2 in human liver microsomes was estimated from the degree of inhibition by ketoconazole, a potent inhibitor of CYP3A. All enzyme activities were measured at an EE 2 substrate concentration of 0.1 mM, which is under a nearly linear condition (Ͻ1/23 of K m values for the respectiv...

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The effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive

Cited by 101 publications

References 31 publications

Failure of Implanon® on antituberculous therapy

Failure of Implanon® on antituberculous therapy

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

Interindividual Variability in 2-Hydroxylation, 3-Sulfation, and 3-Glucuronidation of Ethynylestradiol in Human Liver

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The effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive

Cited by 101 publications

References 31 publications

Failure of Implanon&reg; on antituberculous therapy

Failure of Implanon&reg; on antituberculous therapy

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

Interindividual Variability in 2-Hydroxylation, 3-Sulfation, and 3-Glucuronidation of Ethynylestradiol in Human Liver

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Failure of Implanon® on antituberculous therapy

Failure of Implanon® on antituberculous therapy