Absence of Effect of Oral Rifaximin on the Pharmacokinetics of Ethinyl Estradiol/Norgestimate in Healthy Females

Trapnell, Carol Braun; Connolly, Margaret; Pentikis, Helen S.; Forbes, William; Bettenhausen, Doug

doi:10.1345/aph.1h395

Cited by 35 publications

(26 citation statements)

References 12 publications

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“…Previous studies revealed CYP3A4 induction by RIFax in a human hepatocyte model. Two clinical studies that used MDZ and an oral contraceptive containing ethinyl estradiol and norgestimate (Trapnell et al, 2007) demonstrated that RIFax did not alter the pharmacokinetics of these drugs, indicating that RIFax had no significant effect on intestinal or hepatic CYP3A4 (http://www.salix.com/). However, in the current study, intestinal CYP3A11 was significantly up-regulated in hPXR mice treated with RIFax.…”

Section: Rifaximin Is a Gut-specific Human Pxr Activator 395mentioning

confidence: 99%

Rifaximin Is a Gut-Specific Human Pregnane X Receptor Activator

Shah

Guo

et al. 2007

J Pharmacol Exp Ther

113

107

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Rifaximin, a rifamycin analog approved for the treatment of travelers' diarrhea, is also beneficial in the treatment of multiple chronic gastrointestinal disorders. However, the mechanisms contributing to the effects of rifaximin on chronic gastrointestinal disorders are not fully understood. In the current study, rifaximin was investigated for its role in activation of the pregnane X receptor (PXR), a nuclear receptor that regulates genes involved in xenobiotic and limited endobiotic deposition and detoxication. PXR-humanized (hPXR), Pxr-null, and wild-type mice were treated orally with rifaximin, and rifampicin, a well characterized human PXR ligand. Rifaximin was highly concentrated in the intestinal tract compared with rifampicin. Rifaximin treatment resulted in significant induction of PXR target genes in the intestine of hPXR mice, but not in wild-type and Pxr-null mice. However, rifaximin treatment demonstrated no significant effect on hepatic PXR target genes in wild-type, Pxr-null, and hPXR mice. Consistent with the in vivo data, cell-based reporter gene assay revealed rifaximin-mediated activation of human PXR, but not the other xenobiotic nuclear receptors constitutive androstane receptor, peroxisome proliferator-activated receptor (PPAR)␣, PPAR␥, and farnesoid X receptor. Pretreatment with rifaximin did not affect the pharmacokinetics of the CYP3A substrate midazolam, but it increased the C max and decreased T max of 1Ј-hydroxymidazolam. Collectively, the current study identified rifaximin as a gut-specific human PXR ligand, and it provided further evidence for the utility of hPXR mice as a critical tool for the study of human PXR activators. Further human studies are suggested to assess the potential role of rifaximin-mediated gut PXR activation in therapeutics of chronic gastrointestinal disorders.

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Section: Rifaximin Is a Gut-specific Human Pxr Activator 395mentioning

confidence: 99%

Rifaximin Is a Gut-Specific Human Pregnane X Receptor Activator

Shah

Guo

et al. 2007

J Pharmacol Exp Ther

113

107

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“…An example is a recent study of rifaximin. 3 This is a rifamycin similar to rifampicin, but less than 1 per cent of a dose is absorbed orally and it is used for gastrointestinal infections. Because of its poor absorption, it would not be expected to induce the metabolism of ethinyloestradiol, as does rifampicin.…”

Section: Pharmacokinetic Interaction Studiesmentioning

confidence: 99%

Drug interactions and hormonal contraception

Lee

2009

Trends Urology, Gynecol. Sexual Health

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Predicting drug interactionsGone are the days when drug interactions were picked up only retrospectively, after a medicine was in widespread clinical use. With increasing understanding of drug metabolism and interaction mechanisms, studies are now carried out before a new medicine is approved. From these, a reasonable prediction can usually be made about how likely it is that the new medicine will interact with established drugs, especially for those interactions occurring via the cytochrome P450 (CYP) isoenzyme system of drug metabolism. Nevertheless, some mechanisms of metabolism are less well understood (eg glucuronidation), and unexpected interactions sometimes occur, so we still need to be alert to the possibility of a drug interaction when events are unforeseen.

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“…Rifaximin is used in the treatment of irritable bowel syndrome and is structurally similar to other rifamycins. Not surprisingly, rifaximin is a PXR activator in vitro but uncharacteristically, it does not cause inductive drug interactions as was demonstrated in the absence of effect on either ethinylestradiol or midazolam pharmacokinetics Trapnell et al, 2007). Here, the lack of in vivo inductive effect is related to the fact that rifaximin is not absorbed to any great extent into the systemic circulation to cause an elevation of hepatic drug elimination .…”

Section: Drugs and Herbal Medicines Involved In Clinically Relevantmentioning

confidence: 82%

Impact of Nuclear Receptors CAR, PXR, FXR, and VDR, and Their Ligands On Enzymes and Transporters

Tirona

2009

Enzyme- And Transporter-Based Drug-Drug Interactions

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Nuclear receptors play a central role on the mechanism of inductiontype drug-drug interactions by acting as xenosensing transcription factors. Together, PXR, CAR, FXR, and VDR form a core group of nuclear receptors that regulate the expression of a number of important drug-metabolizing enzymes and drug transporters. In this chapter, the molecular determinants of adaptive response to drug exposure are detailed in the context of clinical relevance and drug development.

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Absence of Effect of Oral Rifaximin on the Pharmacokinetics of Ethinyl Estradiol/Norgestimate in Healthy Females

Abstract: Administration of a 3 day dosing regimen of oral rifaximin was well tolerated and did not alter the pharmacokinetics of a commonly used combination OC containing EE and norgestimate.

Cited by 35 publications

References 12 publications

Rifaximin Is a Gut-Specific Human Pregnane X Receptor Activator

Rifaximin Is a Gut-Specific Human Pregnane X Receptor Activator

Drug interactions and hormonal contraception

Impact of Nuclear Receptors CAR, PXR, FXR, and VDR, and Their Ligands On Enzymes and Transporters

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