The effect of rifampin administration on the disposition of fexofenadine

Hamman, Mitchell A.; Bruce, Melissa A.; Haehner‐Daniels, Barbara D.; Hall, Stephen D.

doi:10.1067/mcp.2001.113697

Cited by 194 publications

(150 citation statements)

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“…RIF regimen 2 (76.0 ml/min/kg). The mean point estimates for AZI and CLARI were 0.96 and 0.94, Additional studies were conducted to determine whether RIF induction of metabolizing enzymes and/or transporters in rats-because induction has been reported for the structurally related analog rifampicin (Fromm et al, 1996;Greiner et al, 1999;Hamman et al, 2001) (also referred to as rifampin)-may partially explain the effects of RIF on the p.o. DNAUC of AZI and CLARI.…”

Section: Investigation Of Possible Systemic Effects On Po Rif Dosinmentioning

confidence: 99%

Involvement of Intestinal Uptake Transporters in the Absorption of Azithromycin and Clarithromycin in the Rat

Garver¹,

Hugger²,

Shearn³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Macrolide antibiotics azithromycin (AZI) and clarithromycin (CLARI) are large molecular weight compounds and are substrates for apically polarized efflux transporters such as P-glycoprotein, which can potentially restrict intestinal absorption. However, despite these undesired physicochemical and biopharmaceutical properties, AZI and CLARI exhibit moderate to excellent p.o. bioavailability in preclinical species and humans. Intestinal uptake transporters, such as organic anion transporting polypeptides (OATPs), can facilitate the uptake of drugs that are substrates and hence increase p.o. absorption. The present study was designed to determine whether the intestinal Oatps are involved in absorption of these macrolides. Macrolide antibiotics azithromycin (AZI) and clarithromycin (CLARI) are predicted by Lipinski's "rule of 5" (Lipinski et al., 1997) to have poor permeation or absorption because of their large molecular weight and hydrogen bonding potential; however, these macrolides show moderate to excellent p.o. exposure in preclinical species and humans. For example, AZI exhibits 46, 97, and 37% p.o. bioavailability in rats, dogs (Shepard and Faulkner, 1990), and humans (Foulds et al., 1990), respectively, even though AZI does not conform to Lipinski rules with its molecular mass of 749 Da, 5 H-bond donors, and 14 H-bond acceptors (Lipinski et al., 1997). Lipinski et al. (1997) suggest that some therapeutic classes such as antibiotics contain orally active drugs because they are substrates for naturally occurring transporters. Both macrolides have been reported to be substrates for the apically polarized efflux transporter P-glycoprotein (P-gp), which can restrict intestinal permeation (Pachot et al., 2003;Sugie et al., 2004). The biliary and intestinal excretion of AZI in the rat has been reported to be mediated by P-gp and multidrug resistance-associated protein 2 (Sugie et al., 2004). CLARI has also been reported to be an inhibitor of CYP3A4 and P-gp (Sugie et al., 2004). Although the metabolism, distribution, and excretion pathways have been investigated for AZI and CLARI, the mechanism of intestinal absorption for these macrolides has not been fully investigated.The organic anion transporting polypeptides (OATPs) comprise a superfamily of sodium-independent transporters that facilitate the transport of endogenous compounds and structurally diverse xenobiotics (Kim, 2003;Hagenbuch and Meier, 2004). These transporters are widely distributed throughout the body, particularly in tissues responsible for mediating the absorption, distribution, metabolism, and excretion properties of drugs, such as the liver, kidney, brain, and intestine (Tamai et al., 2000). OATPs within the same family (e.g., OATP1, OATP2) share Ն40% amino acid sequence identities, whereas members in the same subfamily (e.g., OATP1A, OATP1B) have Ն60% amino acid sequence identities (Hagenbuch and Meier, 2004). Currently, 11 human OATPs and 14 rat Oatps have been identified (Marzolini et al., 2004). In humans, OATP1B1 (or OATP-C) and O...

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Section: Investigation Of Possible Systemic Effects On Po Rif Dosinmentioning

confidence: 99%

Involvement of Intestinal Uptake Transporters in the Absorption of Azithromycin and Clarithromycin in the Rat

Garver¹,

Hugger²,

Shearn³

et al. 2008

Drug Metab Dispos

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“…Pgp is currently the most well understood drug transporter with respect to its regulation, tissue-specific expression, substrate specificity, and modulation of its function by inhibitors (Cvetkovic et al, 1999;Schwarz et al, 1999Schwarz et al, , 2000Drewe et al, 2000;Westphal et al, 2000a;Chiou et al, 2001;Lin et al, 2001;Tayrouz et al, 2001) or inducers (Westphal et al, 2000b;Hamman et al, 2001;Niemi et al, 2001) both in vitro and in vivo. Pgp has been shown to be an important drug efflux transporter in the intestine, liver, brain, and other epithelial tissues and is documented to be involved in clinically significant drug interactions.…”

Section: Table 15mentioning

confidence: 99%

THE CONDUCT OF IN VITRO AND IN VIVO DRUG-DRUG INTERACTION STUDIES: A PHARMACEUTICAL RESEARCH AND MANUFACTURERS OF AMERICA (PhRMA) PERSPECTIVE

Callaghan²,

et al. 2003

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches, to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (P450) probe substrates, inhibitors and inducers and for the development of classification systems to improve the communication of risk to health care providers and to patients. While existing guidances cover mainly P450-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently, and should also be addressed. This article was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.Drug-drug interactions can lead to severe side effects and have resulted in early termination of development, refusal of approval, severe prescribing restrictions, and withdrawal of drugs from the market. Regulators, including the U.S. Food and Drug Administration (FDA 1 ) have therefore issued guidances for in vitro and in vivo drug interaction studies to be conducted during development. These guidances, however, do not address the specific designs of the studies, and there is a desire by regulatory authorities to harmonize approaches and study designs to allow for a better assessment and comparison of different drugs. In addition, the existing guidances cover mainly cytochrome P450 (P450)-mediated drug interactions and the importance of other mechanisms, such as transporters, has been recognized only recently. To address these issues, workshops have been held in

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“…Considering the nearly parallel expression pattern of ABCB1 and PXR along the intestine (own unpublished mRNA data), it is not surprising that co-administration of prototypic enzyme/transporter inducers such as rifampicin or St. John's wort results in substantial DDIs (3,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The same is true for inhibition of ABCB1 for example by macrolide antibiotics (Table I).…”

Section: Potential Implications Of Intestinal Expression Datamentioning

confidence: 71%

“…1). Thus, co-administration of inducers or inhibitors and substrates of these proteins were shown to cause clinically relevant drugdrug interactions (DDIs , Table I) (3,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Moreover, several uptake carriers from the SLC transporter family have been reported to mediate the intestinal uptake of many endogenous compounds (e.g.…”

Section: Introductionmentioning

confidence: 99%

Mass Spectrometry-Based Targeted Proteomics as a Tool to Elucidate the Expression and Function of Intestinal Drug Transporters

Oswald

Gröer

Droździk

et al. 2013

AAPS J

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Abstract. Intestinal transporter proteins affect the oral bioavailability of many drugs in a significant manner. In order to estimate or predict their impact on oral drug absorption, data on their intestinal expression levels are needed. So far, predominantly mRNA expression data are available which are not necessarily correlated with the respective protein content. All available protein data were assessed by immunoblotting techniques such as Western blotting which both possess a number of limitations for reliable protein quantification. In contrast to this, mass spectrometry-based targeted proteomics may represent a promising alternative method to provide comprehensive protein expression data. In this review, we will summarize so far available intestinal mRNA and protein expression data for relevant human multidrug transporters. Moreover, recently observed mass spectrometry-based targeted proteomic data will be presented and discussed with respect to potential functional consequences. Associated to this, we will provide a short tutorial how to set up these methods and emphasize critical aspects in method development. Finally, potential limitations and pitfalls of this emerging technique will be discussed. From our perspective, LC-MS/MS-based targeted proteomics represents a valuable new method to comprehensively analyse the intestinal expression of transporter proteins. The resulting expression data are expected to improve our understanding about the intestinal processing of drugs.

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The effect of rifampin administration on the disposition of fexofenadine

Abstract: This study showed that rifampin effectively increased fexofenadine oral clearance and that this effect was independent of age and sex. We conclude that the cause of the increased oral clearance of fexofenadine is a reduced bioavailability caused by induction of intestinal P-glycoprotein.

Cited by 194 publications

References 13 publications

Involvement of Intestinal Uptake Transporters in the Absorption of Azithromycin and Clarithromycin in the Rat

Involvement of Intestinal Uptake Transporters in the Absorption of Azithromycin and Clarithromycin in the Rat

THE CONDUCT OF IN VITRO AND IN VIVO DRUG-DRUG INTERACTION STUDIES: A PHARMACEUTICAL RESEARCH AND MANUFACTURERS OF AMERICA (PhRMA) PERSPECTIVE

Mass Spectrometry-Based Targeted Proteomics as a Tool to Elucidate the Expression and Function of Intestinal Drug Transporters

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