Quantitative mechanistic studies in simultaneous fluid flow and intestinal absorption using steroids as model solutes

Abstract

The interplay of flow-rate, aquec.rs boundary layer and membrane permeability coefficients, solute lipophilicity and intes'inal length has been quantitatively determined for the in situ situation of bulk fluid flow and concurrent steady-state absorption of steroids in the small intestines of the rat. Seven steroids ranging in 3 orders of magnitude in n-octanol/water partition coefficients were used. The results followed the physical model predictions described by: where C(Q)/C(O) is the fraction of steroid remaining in the intestinal lumen of length Q, r is the effective lumenal radius, Q is the flow-rate, Pi,9 and Pm are the respective aqueous boundary layer and membrane permeability coefficients. The log fraction of steroids remaining in the lumen was linear with intestinal length at various flow rates. The fraction absorbed increased with slower flow-rates at any given length due to the longer resi lence time. The fraction of steroid absorbed vs log partition coefficient profiles as a functjon of flow-rate were significantly sigmoidal. The absorption rates of progesterone were aqueous boundary layer-controlled and the less lipophiic hydrocortisone were membrane-controlled. It is significant that the permeability of the aqueous boundary layer is proportional to Q"*44 .

Determination of Regional Intestinal Permeability of Diclofenac and Metoprolol Using a Newly-Developed and Validated High Performance Liquid Chromatographic Method

“…R is the radius of the perfused intestinal segment (for jejunum and ileum R = 0.2 cm, for colon R = 0.25); L is the length of the intestinal segment (cm) [3,15,16].…”

Significance and Regional Dependency of Peptide Transporter (PEPT) 1 in the Intestinal Permeability of Glycylsarcosine: In Situ Single-Pass Perfusion Studies in Wild-Type andPept1Knockout Mice

“…The effective permeability (P eff ) was determined from the steady-state loss of drug from the perfusate as it flows through the intestine, according to a complete radial mixing (parallel tube) model (Komiya et al, 1980;Kou et al, 1991).…”

Application of Method Suitability for Drug Permeability Classification

“…The in situ perfusion model allows for the measurement of drug permeability in the intact intestine by single-pass and recirculating methods (42)(43)(44) (Table III). For the single-pass (open loop) perfusion method, a section of intestine in an anesthetized animal is cannulated proximally and distally, rinsed with buffer solution, and then perfused with a drug solution.…”