Article pubs.acs.org/molecularpharmaceutics
Regional Intestinal Permeability of Three Model Drugs in Human David Dahlgren,† Carl Roos,† Anders Lundqvist,‡ Bertil Abrahamsson,‡ Christer Tannergren,‡ Per M. Hellström,§ Erik Sjögren,† and Hans Lennernas̈ *,† †
Department of Pharmacy, Uppsala University, Uppsala SE-751 23, Sweden AstraZeneca R&D, Gothenburg, Sweden § Department of Medical Sciences, Uppsala University, Uppsala SE-751 05, Sweden ‡
ABSTRACT: Currently there are only a limited number of determinations of human Peff in the distal small intestine and none in the large intestine. This has hindered the validation of preclinical models with regard to absorption in the distal parts of the intestinal tract, which can be substantial for BCS class II−IV drugs, and drugs formulated into modified-release (MR) dosage forms. To meet this demand, three model drugs (atenolol, metoprolol, and ketoprofen) were dosed in solution intravenously, and into the jejunum, ileum, and colon of 14 healthy volunteers. The Peff of each model drug was then calculated using a validated deconvolution method. The median Peff of atenolol in the jejunum, ileum, and colon was 0.45, 0.15, and 0.013 × 10−4 cm/s, respectively. The corresponding values for metoprolol were 1.72, 0.72, and 1.30 × 10−4 cm/s, and for ketoprofen 8.85, 6.53, and 3.37 × 10−4 cm/s, respectively. This is the first study where the human Peff of model drugs has been determined in all parts of the human intestinal tract in the same subjects. The jejunal values were similar to directly determined values using intestinal single-pass perfusion, indicating that the deconvolution method is a valid approach for determining regional Peff. The values from this study will be highly useful in the validation of preclinical regional absorption models and in silico tools. KEYWORDS: intestinal permeability, regional intestinal drug absorption, effective permeability, pharmacokinetics
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INTRODUCTION The rate and extent of intestinal absorption of an orally administered dosage form is determined by biopharmaceutical properties, such as the dissolution rate of the drug product, the solubility of the active pharmaceutical ingredient (API), luminal stability, and permeability across the epithelial barrier at different intestinal sites. Effective permeability (Peff) is one of the key parameters in the biopharmaceutics classification system (BCS), and represents the rate at which a drug compound is transported across the intestinal membrane.1 Peff is determined and calculated in different ways, but represents overall transepithelial transport rate. This is regardless of the transport mechanism, which is often a combination of passive bilayer lipoidal diffusion, passive paracellular diffusion, and active or facilitated carrier-mediated (CM) membrane transport in any direction.2 The gastrointestinal (GI) tract is physiologically and gross-anatomically divided into five regions: the stomach, the proximal small intestine (jejunum), the distal small intestine (ileum), the large intestine (colon), and the rectum. Of these regions the jejunum and ileum are the main sites for drug and nutrient absorption. The fraction of an oral dose absorbed ( fabs) from the stomach is generally very low, but can be up to 20−40% for small, uncharged molecules under certain conditions.3 Drug permeability is substantially higher in the small intestine (SI) than in the colon, at least for lowpermeability compounds.4 However, the colon is an important absorptive organ for modified-release (MR) dosage forms of © 2016 American Chemical Society
drugs and potentially also for BCS class III and IV drugs, which are incompletely absorbed in the SI. Single-pass intestinal perfusion has been instrumental in understanding human in vivo mechanisms of biopharmaceutical processes such as solubility, dissolution, precipitation, efflux, gut wall metabolism, and permeability.5 Currently only jejunal single-pass Peff values are determined and used to correlate various intestinal absorption models for humans.3 In vivo Peff values from the distal intestine would therefore be highly valuable for evaluating preclinical and theoretical simulation models of intestinal absorption of orally administered drugs.6 An increased understanding of the underlying differences in transport processes and their variations at different intestinal sites would aid decision-making in the pharmaceutical design of novel drug compounds and MR formulations. This would mitigate the risk of costly, late-stage attrition of drug candidates due to insufficient colonic permeability. The determination of regional intestinal Peff in human is therefore fundamental for predictive model validation. To this end, we conducted a clinical intubation study to determine the regional intestinal Peff of three physicochemically diverse model drugs (atenolol, metoprolol, and ketoprofen) in Received: Revised: Accepted: Published: 3013
June 20, 2016 August 8, 2016 August 9, 2016 August 9, 2016 DOI: 10.1021/acs.molpharmaceut.6b00514 Mol. Pharmaceutics 2016, 13, 3013−3021
Article
Molecular Pharmaceutics
Table 1. Physicochemical Properties, BCS (Biopharmaceutics Classification System) Classification, and Human Jejunal Effective Permeability (Peff) Historically Determined with Intestinal Perfusion of the Three Model Drugs5,26 substance (BCS class) atenolol (III) metoprolol (I) ketoprofen (II)
MMa (g/mol) 266 267 254
pKab g
9.6 9.6g 3.89h
PSAc
HBA/HBDd
LogPe
LogD7.4f
LogD6.5f
Peff (×10−4 cm/s)
88.1 57.8 54.2
4/4 4/2 3/1
0.18 2.07 3.37
−2.0 0.0 0.1
116.2, 255.1 > 105.0, and 455.3 > 165.0, respectively. Instrument control, data acquisition, and data evaluation were performed using Agilent MassHunter. The calibration ranges for atenolol, metoprolol, and ketoprofen were 0.3−950 nM, 0.3−800 nM, and 0.3−1200 nM, respectively. The relative standard deviation for the LLOQ was
