A comprehensive account on the role of efflux transporters in the gastrointestinal absorption of 13 commonly used substrate drugs in humans

Chiou, Win L.; Chung, Sung Kee; Wu, Ta C.; Ma, Chien

doi:10.5414/cpp39093

Cited by 104 publications

(65 citation statements)

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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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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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“…There appears to be a good correlation between in-vitro and in-vivo permeability for drugs with passive diffusion as the main transport mechanism, but there is a significant deviation for drugs absorbed through transporters Lennerna¨s 1997Sun et al 2002). It is also considered that the interpretation of the importance of efflux carrier on intestinal absorption process is overrated based on results obtained in tissue cell cultures (e.g., Caco-2 cells) (Lennernas 1998(Lennernas , 2003Chiou et al 2001;Yu et al 2002;Tannergren et al 2003a, b;Petri et al 2004). For instance, based on only cell culture data (Caco-2 cells), it was shown that the in-vitro permeability of fexofenadine in the absorptive direction increased by approximately 200-300% in the presence of various P-glycoprotein (Pgp) inhibitors, such as verapamil, ketoconazole and GF 120918, and that low passive diffusion was the main reason for the incomplete and variable intestinal absorption ( Figure 3A) (Petri et al 2004).…”

Section: Bcs In the Early Drug Development Phasementioning

confidence: 99%

The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension

Lennernäs

Abrahamsson

2005

Journal of Pharmacy and Pharmacology

184

119

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Bioavailability (BA) and bioequivalence (BE) play a central role in pharmaceutical product development and BE studies are presently being conducted for New Drug Applications (NDAs) of new compounds, in supplementary NDAs for new medical indications and product line extensions, in Abbreviated New Drug Applications (ANDAs) of generic products and in applications for scale-up and post-approval changes. The Biopharmaceutics Classification System (BCS) has been developed to provide a scientific approach for classifying drug compounds based on solubility as related to dose and intestinal permeability in combination with the dissolution properties of the oral immediaterelease (IR) dosage form. The aim of the BCS is to provide a regulatory tool for replacing certain BE studies by accurate in-vitro dissolution tests. The aim of this review is to present the status of the BCS and discuss its future application in pharmaceutical product development. The future application of the BCS is most likely increasingly important when the present framework gains increased recognition, which will probably be the case if the BCS borders for certain class II and III drugs are extended. The future revision of the BCS guidelines by the regulatory agencies in communication with academic and industrial scientists is exciting and will hopefully result in an increased applicability in drug development. Finally, we emphasize the great use of the BCS as a simple tool in early drug development to determine the rate-limiting step in the oral absorption process, which has facilitated the information between different experts involved in the overall drug development process. This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in drug molecules with a sufficiently high permeability, solubility and dissolution rate, and that will automatically increase the importance of the BCS as a regulatory tool over time.

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“…P-gp has an effect on the pharmacokinetics of a variety of anticancer drugs and other drugs including digoxin [3], HIV protease inhibitors [4], statins [5], antihistamines [6] and numerous other drugs and xenobiotics.…”

Section: Introductionmentioning

confidence: 99%

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

et al. 2006

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Introduction-The human multi-drug resistance gene (MDR1, ABCB1) codes for P-glycoprotein (P-gp), an important membrane-bound efflux transporter known to confer anti-cancer drug resistance as well as affect the pharmacokinetics of many drugs and xenobiotics. A number of single nucleotide polymorphisms (SNPs) have been identified throughout the ABCB1 gene which may have an effect on P-gp expression levels and function. Haplotype as well as genotype analysis of SNPs is becoming increasingly important in identifying genetic variants underlying susceptibility to human disease. Three SNPs, 1236C>T, 2677G>T, and 3435C>T have been repeatedly shown to predict changes in the function of P-gp. The frequencies with which these polymorphisms exist in a population have also been shown to be ethnically related.

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A comprehensive account on the role of efflux transporters in the gastrointestinal absorption of 13 commonly used substrate drugs in humans

Cited by 104 publications

References 0 publications

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

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

The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

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