Effect of Common Excipients on Intestinal Drug Absorption in Wistar Rats

Abstract

The aim of the present paper is to study the effect of common excipients on the permeability of atenolol (as drug absorbed mainly by passive diffusion) and rhodamine (as P-glycoprotein substrate). The apparent permeability was measured by an in situ perfusion method in Wistar rats using the closed loop Doluisio’s method. Permeability values were characterized in the absence and presence of 18 commonly used excipients. Excipient concentrations were selected based on the amounts in oral immediate release dosage forms, which failed the test during the human bioequivalence studies. Atenolol was studied with and without excipients in the whole small intestine, whereas rhodamine was tested in three different intestinal segments to account for the differential expression of P-glycoprotein, and it was further on tested in the ileum, in the presence of excipients. Atenolol presented higher permeability values when it was administered with colloidal silica, croscarmellose, hydroxypropyl methylcellulose (HPMC), magnesium stearate, MgCO3, poly­(ethylene glycol) 400, poly­(vinylpyrrolidone), sorbitol, starch, and TiO2 rhodamine showed higher permeability values when it was administered with croscarmellose and HPMC. On the one hand, the mechanisms of action were not discernible with the proposed experiments. On the other hand, commercial formulations do not present a single excipient but several, which can counteract their effects. The in situ perfusion technique can be useful for a preliminary screening and risk analysis, while the in vivo pharmacokinetic results would be needed to define conclusive effects.

An Assessment of Occasional Bio-Inequivalence for BCS1 and BCS3 Drugs: What are the Underlying Reasons?

“…The impact of excipients on the pharmacokinetics of BCS1/3 drugs is a subject which has caused much controversy in the literature, with advocates on one side of the debate some pointing to data where small changes in excipient levels were correlated with PK change in human BE studies 29,30,56 , data from cell line measurements [57][58][59][60][61] or in-situ animal perfusion studies 57,62 where excipients have altered drug permeability as evidence that even small changes in excipient levels can lead to inequivalence.…”

Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling to Support Waivers of In Vivo Clinical Studies: Current Status, Challenges, and Opportunities

“…In addition, the relative contribution and specific effects of food components (lipids, proteins, carbohydrates) need to be investigated further . Other considerations include possible inhibitory effects on intestinal permeability, enzymes, or transporters (e.g., CYP3A4, OATP2B1, Pgp, BCRP), increased splanchnic blood flow, and gut microbiome interaction with micellar structures. ,,, Recent research has demonstrated the effect of several excipients and food additives on the inhibition of uptake and efflux transporters in the gut, especially of OAT12B1 and Pgp, in vitro , in situ , or in animal species. − Other studies have shown that bacterial metabolism from gut microbiota could counterbalance this effect by metabolizing susceptible excipients to inactive metabolites . At the same time, some excipients have been found capable of enhancing drug permeation across the enterocyte apical membrane in vitro .…”

Decreased Penetration Mechanism of Ranitidine Due to Application of Sodium Sulfobutyl Ether-β-Cyclodextrin

“…According to the International Coordination Committee for the Registration of Pharmaceutical Products for Human Use (ICH) guidelines and the M9 Bioequivalence Exemptions Based on the Biopharmaceutical Classification System [1][2][3][4] permeability is closely related to the rate and extent of drug absorption in the body and is one of the key factors in the transport of drugs in the body through expanded membranes and is relevant to drug development. Pharmaceutical excipients are non-physiologically active substances in pharmaceuticals that affect their absorption and bioavailability in the body [5][6][7]. For poorly permeable drugs, permeation enhancers are commonly used [8][9][10][11], for example, fatty alcohols, which increase drug permeability by altering the structure and properties of biofilms.…”