Effect of Common Excipients on Caco-2 Transport of Low-Permeability Drugs

Rege, Bhagwant D.; Yu, Lawrence X.; Hussain, Ajaz; Polli, James E.

doi:10.1002/jps.1127

Cited by 171 publications

(129 citation statements)

References 17 publications

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“…The P app values obtained for propranolol are in agreement with values reported in the literature 11) for this highly permeable compound, but for ranitidine the values reported in the literature 12) are slightly higher than what we obtained, which is probably attributable to analytical precision and accuracy due to its very low permeability. Loratadine added to the mixture with propranolol and ranitidine appeared to have significantly lower permeability than when studied alone suggesting interference of either propranolol or ranitidine or both these compounds with permeability of loratadine.…”

Section: Discussionsupporting

confidence: 91%

Classification of Loratadine Based on the Biopharmaceutics Drug Classification Concept and Possible in Vitro-in Vivo Correlation

Khan

Raušl

Zanoski

et al. 2004

Biological & Pharmaceutical Bulletin

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Loratadine, chemically known as ethyl 4-(8-chloro-5,6-dihydro-11H-benzo [5,6]-cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate, is a weak base with a pK a value of ca. 6 (calculated in our laboratories). It is absorbed rapidly following oral administration in humans giving maximum plasma concentration (C max ) in about 1-1.5 h when administered under fasting conditions, but the degree of inter-subject variability in the pharmacokinetic parameters was reported to be very high. The C max and plasma concentration-time (AUC t ) data obtained following oral administration of 10 mg, 20 mg, and 40 mg loratadine capsules were found to have a dose-proportional relationship. 3)Following oral dosing 80% of the total dose administered was found equally distributed between urine and faeces in the form of metabolic products within 10 d.4) The kinetics of loratadine observed during a multiple dose study were found comparable to those reported from single dose studies, but the mean plasma concentration-time data were approximately 90% greater than that reported for single dose data, and the steady state plasma concentrations were apparent by the fifth day of dosing. 5)The objective of the studies reported here was two fold; firstly, to classify loratadine according to the biopharmaceutics drug classification scheme, 6,7) and secondly, to compare plasma time profiles predicted from in vitro dissolution data with experimental plasma time data in order to select the most appropriate conditions for in vitro assessment of loratadine solid dosage forms. Furthermore, attempts have been made to investigate factors responsible for the high inter-subject variability in pharmacokinetic parameters of the drug. MATERIALS AND METHODS MaterialsLoratadine of European Pharmacopoeia (EP) quality was purchased from Chemo Iberica S.A. (Lugano, Switzerland). Standard pharmacopoeial grade excipients were used in the tablet formulation. Egg lecithin used for dissolution studies under biorelevant conditions was a gift from Lipoid AG (Cham, Switzerland). Crude sodium taurocholate (batch no. 386645/1, standardised against a lot of the pure substance containing above 97%) was purchased from Sigma Chemical Co. (St. Louis, U.S.A.). Sodium lauryl sulphate, hydrochloric acid and all other chemicals used for evaluation of the tablets were of analytical grade. The tablets were prepared in-house (by wet granulation technology using starch paste as a binder).For permeability testing, Caco-2 cells were obtained from the European Collection of Cell Cultures (U.K.) at passage 20. Dulbecco's Eagles medium (DMEM) containing glucose (4500 mg/ml) was purchased from Imunološki Zavod, Zagreb (Croatia). Fetal bovine serum (FBS), glutamax I, nonessential amino acids (NEAA), penicillin/streptomycin, fungizone and 0.25% trypsin-EDTA were obtained from Gibco, Life Technologies (U.K.). Hanks balanced salt solution (HBSS) and dimethylsulphoxide (DMSO) were purchased from Sigma-Aldrich (Germany). Tert-butyl methyl ether (TBME) was supplied by Merck (Germany).Solubili...

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Section: Discussionsupporting

confidence: 91%

Classification of Loratadine Based on the Biopharmaceutics Drug Classification Concept and Possible in Vitro-in Vivo Correlation

Khan

Raušl

Zanoski

et al. 2004

Biological & Pharmaceutical Bulletin

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“…However, at present there are few specific transporters characterized. When the objective is to determine the in vivo relevance of efflux proteins to offset passive paracellular and transcellular absorption of drugs, some investigators prefer to use for an apical concentration the clinical dose dissolved in 250 ml or less depending on the solubility of the compound (Rege et al, 2001). …”

Section: Drug Transportersmentioning

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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“…Human studies to determine excipient effects in a dose-response fashion could be considered unethical, not practical, and cost prohibitive. In vitro culture studies using Caco-2 cells have been conducted to determine the effect of some common excipients (8). Briefly, the objective of their work was to evaluate the effect of nine individual excipients on the Caco-2 permeability of seven low-permeable compounds that differ in their physiochemical properties.…”

Section: Introductionmentioning

confidence: 99%

Scientific Perspectives on Extending the Provision for Waivers of In vivo Bioavailability and Bioequivalence Studies for Drug Products Containing High Solubility-Low Permeability Drugs (BCS-Class 3)

Stavchansky

2008

AAPS J

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Abstract. Recently, there has been increased interest in extending the provision for waivers of in vivo bioavailability and bioequivalence (BA-BE) studies that appeared in the guidance published by the Food and Drug Administration (FDA) (1) to pharmaceutical products containing Class 3 drugs (High solubility-Low Permeability). The extension of the Biopharmaceutics Classification System (BCS) to Class 3 drugs is meritorious because of its impact on public health policy considerations. The rate limiting step in the absorption of Class 3 drugs is the permeability through the intestinal membrane. This commentary will focus its attention on the scientific considerations which need to be examined to assess the risk and the benefit prior to granting a waiver of in vivo bioavailability and/or bioequivalence studies for Class 3 drugs. It will examine the forces affecting the interconnectivity of the neuronal, immunological and hormonal systems in the gastrointestinal tract that may affect its permeability and functionality. It will also challenge the assumption that in vitro dissolution and in vitro permeability studies in tissue cultures in the presence and absence of excipients are good predictors for in vivo dissolution and in vivo permeability which are at the heart of the BCS.

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Effect of Common Excipients on Caco-2 Transport of Low-Permeability Drugs

Cited by 171 publications

References 17 publications

Classification of Loratadine Based on the Biopharmaceutics Drug Classification Concept and Possible in Vitro-in Vivo Correlation

Classification of Loratadine Based on the Biopharmaceutics Drug Classification Concept and Possible in Vitro-in Vivo Correlation

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

Scientific Perspectives on Extending the Provision for Waivers of In vivo Bioavailability and Bioequivalence Studies for Drug Products Containing High Solubility-Low Permeability Drugs (BCS-Class 3)

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