Absorption barriers in the rat intestinal mucosa: 2. Application of physiologically based mathematical models to quantify mechanisms of drug permeation and metabolism.
The absorption of drug molecules is often investigated using in vitro or in situ models of the intestinal mucosa; however, few studies have quantified the kinetics that limit absorption. The objective of this study was to quantify kinetic rates of rat intestinal absorption, metabolism, and efflux using nonlinear mixed effects modeling. A multicompartment model accurately described the absorption and distribution of atenolol and verapamil as well as the metabolism of verapamil and distribution of the metabolite, norverapamil. The accurate description of atenolol data required inclusion of an intermediate compartment in addition to paracellular clearance, whereas verapamil and norverapamil were modeled in the absence of paracellular clearance. The absorption of verapamil was well characterized by linear kinetics, whereas the formation and distribution of norverapamil were well characterized by Michaelis-Menten kinetics. The model identified EDTA as a modulator of physical barriers, ketoconazole as an inhibitor of cytochrome P450 3A and P-glycoprotein (P-gp), and PSC-833 and GF-120918 as specific P-gp inhibitors. These results demonstrate the utility of a physiologically based model to characterize (i) the drug distribution across the in situ perfused rat intestine and (ii) the effect of chemical modulators in this biological system.
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 45429, USA. mudrada@lilly.com
Daniel R
DR
Mudra
Jin Y
JY
Jin
Ronald T
RT
Borchardt
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000166:Acridines / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D000465:Algorithms; D000818:Animals; D001262:Atenolol / Q000008:administration & dosage / Q000493:pharmacokinetics; D001711:Biotransformation; D003198:Computer Simulation; D003524:Cyclosporins / Q000494:pharmacology; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007654:Ketoconazole / Q000494:pharmacology; D015233:Models, Statistical; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014700:Verapamil / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000319:Adrenergic beta-Antagonists; D003524:Cyclosporins; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D044005:Tetrahydroisoquinolines; D001262:Atenolol; C016904:norverapamil; D014700:Verapamil; C083501:Elacridar; C070272:valspodar; D007654:Ketoconazole