Determination of drug permeability in a flat or distended stirred intestine. Prediction of fraction dose absorbed in humans after oral administration.
Equations published earlier to calculate intestinal permeability (P) from in situ or in vivo studies and to predict fraction of dose absorbed (F) after oral administration may often be based on some physiologically and pharmacokinetically unrealistic assumptions; for example, (a) the intestine behaving like a "fully" distended, rigid, cylindrical tube without any intrinsic motility or stirring, (b) no accumulation of drug in gut wall or tissue, (c) lack of blood flow effect on permeability, (d) lack of back diffusion from absorptive cell to lumen, (e) a smooth surface area for absorption, and (f) a well-defined luminal concentration profile. An alternative, simple, realistic organ clearance approach is described here to re-define and calculate P as apparent absorptive permeability or absorptive clearance per unit gross surface area and to predict F based on either human or animal data. The approach may prove particularly valuable in view of the insignificant impact of "unstirred" water layer on F. The small intestine in humans and animals is found to be very flat overall (only about 10 of 30% distension in fasting state). The human intestinal luminal flow after normal dosing is estimated at about 3 ml/min, sixfold higher than 0.5 ml/min proposed by others. The direct consequence of an early assumption that dimensionless P is the same between human and rat is pointed out; the permeability coefficient being 7-10 times higher in rats than in humans, that is, however, not supported by experimental data. The apparent success of a widely used approach to estimate F based on rat data is rationalized.(ABSTRACT TRUNCATED AT 250 WORDS)
Chiou
W L
WL
Department of Pharmaceutics and Pharmacodynamics, College of Pharmacy, University of Illinois at Chicago 60612.
D000284:Administration, Oral; D000818:Animals; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D008954:Models, Biological; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism; D010599:Pharmacokinetics; D051381:Rats
D004364:Pharmaceutical Preparations