Predicting Passive Intestinal Absorption Using A Single Parameter

Abstract

A model is proposed for the prediction of either high or low fraction absorbed for an orally administered, passively transported drug on the basis of a new absorption parameter, P. The model includes only two inputs: the octanol-water partition coefficient (K ow ) and the dimensionless oversaturation number (O Lumen ). The latter is the ratio of the concentration of drug delivered to the gastrointestinal (GI) fluid to the solubility of the drug in that environment. Thus, O Lumen is equal to the dose-normalized solubility for suspensions and unity for solutions. The value of P increases with an increase in K ow and a decrease in O Lumen for suspensions, and is equal to K ow for solutions. The effectiveness of the model is validated using experimental human gastrointestinal absorption data for 98 compounds. About 88% of these drugs are correctly predicted to be either well absorbed or poorly absorbed based solely upon whether their P value is greater than or less than unity. Thus, the use of a single absorption parameter, P provides a simple means to estimate whether or not an orally administered drug undergoing passive transport will be absorbed efficiently. The advantage of this parameter is that it is based upon simple, easily measured (or calculated) physical chemical data. It is especially noteworthy that experimental measurement of in vitro membrane transport is not required. The model based on the new absorption parameter is shown to have wider applicability than current available models for predicting the fraction absorbed.

A rule of unity for human intestinal absorption 3: Application to pharmaceuticals

“…Experimental values of oral absorption for a diverse group of pharmaceuticals were obtained from the well‐known critically evaluated human intestinal absorption databases developed by Hou, Wang, Zhang, and Xu () , Newby, Freitas, and Ghafourian () and other scientific literature (Chu & Yalkowsky, ; Sanghvi et al, ; Zhao et al, ). In this work, FA is defined as the fraction of dose absorbed through the GI membrane assuming negligible luminal degradation and first pass metabolism (Dressman et al, ).…”

“…Therefore, whether the drug is forming a solution or a suspension at the administered dose is an important factor for predicting the human intestinal absorption. Sanghvi et al (2003)…”

“…Therefore, whether the drug is forming a solution or a suspension at the administered dose is an important factor for predicting the human intestinal absorption. Sanghvi et al () introduced the rule of unity and developed a new unitless parameter called luminal oversaturation number, O Lumen , which reflects the degree of oversaturation of the GI luminal fluid by drug. It is defined as …”

“…When a drug is administered orally, it can form the solution or suspension in the GI lumen based on its administered dose and its intrinsic solubility. Sanghvi, Ni, Mayersohn, and Yalkowsky (2003) showed that this model could be divided broadly into two categories based on the orally administered dose.…”

A ‘Rule of Unity’ for Human Intestinal Absorption

“…Recently, Sanghvi et al (5) developed a new absorption parameter P which can predict whether or not a drug will be well absorbed (i.e., at least half of the administered drug is absorbed). Using the absorption model described by Stehle and Higuchi (6), Flynn and Yalkowsky (7) and Yalkowsky and Flynn (8), they defined the absorption parameter as the drug's octanolYwater partition coefficient, K ow , divided by its luminal over-saturation number, i.e.,…”