Investigation of Regional Mechanisms Responsible for Poor Oral Absorption in Humans of a Modified Release Preparation of the α-Adrenoreceptor Antagonist, 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4 tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (UK-338,003): The Rational Use of ex Vivo Intestine to Predict in Vivo Absorption

Abstract

ABSTRACT:Modified release (MR) formulations are used to enhance the safety and compliance of existing drugs by improving their pharmacokinetics. Predicting the likely success of MR formulations is often difficult before clinical studies. A systematic in vitro approach using mouse and human tissues was adopted to rationalize the in vivo pharmacokinetics of 9-and 15-h MR formulations of an ␣-adrenoreceptor antagonist, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4 tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (UK-338,003). Immediate release UK-338,003 was well absorbed in humans consistent with moderate Caco-2 cell monolayer permeability. In contrast, 9-and 15-h modified release formulations showed marked reductions in C max (47.1 and 68.9%) and AUC 0-72 (32.6 and 54.0%). Colonic intubation resulted in 81.3 and 73.8% reductions in C max and AUC 0-72 . Mechanistic studies in isolated mouse tissues showed that colonic UK-338,003 permeability (P app < 0.5 ؋ 10 ؊6 cm/s) was at least 40 times lower than that for ileum with marked asymmetry. UK-338,003 was found to be a substrate for P-glycoprotein (PGP) with a weaker interaction for multidrug resistance-associated protein-type transporters in mouse intestine. PGP inhibition dramatically increased colonic UK-338,003 permeability to the levels observed in ileum. Low UK-338,003 apical to basolateral permeability was also observed in ex vivo human distal intestine, but both the asymmetry and increase in permeability after PGP inhibition were significantly lower. In conclusion, the poor absorption of MR UK-338,003 in humans can be explained by a combination of PGP-dependent efflux and low intrinsic permeability in the lower bowel. Regional permeability studies in ex vivo tissues used during drug development can highlight absorption problems in the distal bowel and assess the feasibility of developing successful MR formulations.Oral modified release (MR) formulation can improve the pharmacokinetic and pharmacodynamic properties of a drug and thus lead to both improved patient compliance and safety (Conley et al., 2006). However, predicting the success of MR formulations for a given drug has proved difficult, particularly for drugs with moderate intestinal permeability, and often the success or failure may only become apparent during clinical trials. One of the problems associated with prediction of absorption from a typical 8-to 24-h MR dosage form is that, unlike for immediate release (IR) forms, the drug is released throughout the GI tract with a significant proportion delivered to the distal intestine. As a result, regional differences and, in particular, the efficiency of colonic absorption will be a critical consideration. For a variety of reasons, drug absorption in the colon appears to be more challenging than absorption in the proximal bowel. In physical terms, the colon is a viscous, low-mixing environment with a lower surface area for absorption compared with the proximal bowel. Both paracellular and transcellular permeabilities appear to be lower in th...

Drug transporters in drug discovery and development

“…Generally, net drug absorption is achieved through multiple uptake and effl ux transporters along with passive transcellular diffusion in the intestinal barrier (Lennernas, 2003(Lennernas, , 2007. Effl ux transporters located on the apical brush border membrane of the gastrointestinal (GI) tract, such as P-gp, MRP2 and BCRP, are considered barriers to intestinal drug absorption (Figure 8.3) (Higgins, 2001;Dietrich et al, 2003;Kunta and Sinko, 2004;Tanaka et al, 2005;Collett et al, 2008). On the other hand, various SLC transporters are expressed in enterocytes and involved in the intestinal absorption of therapeutics (Tamai et al, 2000;Walters et al, 2000;Kullak-Ublick and Becker, 2003).…”

Absolute abundance and function of intestinal drug transporters: a prerequisite for fully mechanistic in vitro–in vivo extrapolation of oral drug absorption

“…To obtain kinetic data in human intestinal ex vivo tissues is a considerably greater challenge than in in vitro systems as there are often limited supplies of macroscopically normal fresh human intestinal tissue to quantify abundance and substrate kinetics. Ussing chamber studies are undertaken to elucidate drug transport and to assess regional differences in human functional expression . Bi‐directional permeability experiments in Ussing chambers are routinely performed with n = 2 to 3 samples from a single donor where a subsequent efflux ratio can be determined.…”

The use of gastrointestinal intubation studies for controlled release development

“…Alternative methods to intubation are reviewed in the literature and will not be discussed here [27]. The purpose of this study is not to compare and contrast those methods or alternative intubation techniques [28–30] with those included in this manuscript. Rather by review of our experience, this study shows that some method to estimate a candidate's bioavailability after administration to the colon is helpful in the development for CR formulations.…”