Correlation between Net Water Flux and Absorptive Clearance Determined from In Situ Intestinal Perfusion Studies Does Not Necessarily Indicate a Solvent Drag Effect

Estimation of absorptive clearance (PeA) of drugs from in situ perfusion studies, based on the disappearance of drugs from the intestinal lumen, involves correcting outflow perfusate drug concentration with net water flux (Jw). However, as demonstrated through both theoretical derivations and simulations, the PeA estimated from a nonlinear equation approximates a linear relationship with Jw for a low permeability drug, regardless of whether or not Jw has a real effect on PeA. As such, a correlation between Jw and PeA is less meaningful as an indicator of a solvent drag effect. Moreover, from the linear relationship, the slope of the Jw-PeA correlation plot (defined as the sieving coefficient) equals the ratio of outflow versus inflow perfusate drug concentrations and can be greater than unity when more water than drug is absorbed during perfusion studies. The intercept of the correlation plot can be below zero if this occurs.