Human in vivo regional intestinal permeability: quantitation using site-specific drug absorption data.
Application of information on regional intestinal permeability has been identified as a key aspect of successful pharmaceutical product development. This study presents the results and evaluation of an approach for the indirect estimation of site-specific in vivo intestinal effective permeability (Peff) in humans. Plasma concentration-time profiles from 15 clinical studies that administered drug solutions to specific intestinal regions were collected and analyzed. The intestinal absorption rate for each drug was acquired by deconvolution, using historical intravenous data as reference, and used with the intestinal surface area and the dose remaining in the lumen to estimate the Peff. Forty-three new Peff values were estimated (15 from the proximal small intestine, 11 from the distal small intestine, and 17 from the large intestine) for 14 active pharmaceutical ingredients representing a wide range of biopharmaceutical properties. A good correlation (r(2) = 0.96, slope = 1.24, intercept = 0.030) was established between these indirect jejunal Peff estimates and jejunal Peff measurements determined directly using the single-pass perfusion double balloon technique. On average, Peff estimates from the distal small intestine and large intestine were 90% and 40%, respectively, of those from the proximal small intestine. These results support the use of the evaluated deconvolution method for indirectly estimating regional intestinal Peff in humans. This study presents the first comprehensive data set of estimated human regional intestinal permeability values for a range of drugs. These biopharmaceutical data can be used to improve the accuracy of gastrointestinal absorption predictions used in drug development decision-making.
Department of Pharmacy, Biopharmaceutic Research Group, Uppsala University, SE-751 23 Uppsala, Sweden.
Erik
E
Sjögren
Department of Pharmacy, Biopharmaceutic Research Group, Uppsala University, SE-751 23 Uppsala, Sweden.
David
D
Dahlgren
Department of Pharmacy, Biopharmaceutic Research Group, Uppsala University, SE-751 23 Uppsala, Sweden.
Carl
C
Roos
Department of Pharmacy, Biopharmaceutic Research Group, Uppsala University, SE-751 23 Uppsala, Sweden.
Hans
H
Lennernäs
D019819:Budesonide / Q000493:pharmacokinetics; D003106:Colon / Q000166:cytology; D016572:Cyclosporine / Q000493:pharmacokinetics; D011345:Fenofibrate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D000069478:Lisdexamfetamine Dimesylate / Q000493:pharmacokinetics; D008790:Metoprolol / Q000493:pharmacokinetics; D009543:Nifedipine / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000493:pharmacokinetics; D011899:Ranitidine / Q000493:pharmacokinetics; D000068836:Rivastigmine / Q000493:pharmacokinetics; D018170:Sumatriptan / Q000493:pharmacokinetics; D016593:Terfenadine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D013806:Theophylline / Q000493:pharmacokinetics
D011743:Pyrimidines; D019819:Budesonide; C043077:ipsapirone; D016593:Terfenadine; D016572:Cyclosporine; D011899:Ranitidine; D018170:Sumatriptan; C006012:fenofibric acid; D013806:Theophylline; C093230:fexofenadine; D008790:Metoprolol; D009543:Nifedipine; D000068836:Rivastigmine; D000069478:Lisdexamfetamine Dimesylate; D011345:Fenofibrate
colon; human in vivo intestinal permeability; regional permeability; site-specific permeability