Determination of the passive absorption through the rat intestine using chromatographic indices and molar volume.

Immobilized artificial membrane (IAM) chromatography coupled to physicochemical descriptors was evaluated to model the passive intestinal absorption of drugs through rat gut sacs. The chromatographic capacity factors (logk'(IAM)) of 12 structurally diverse compounds were determined on a IAM PC DD2 column. The passive permeabilities (P(a)) of the drugs were determined through rat everted gut sacs or through non-everted sacs for actively transported molecules. Correlation studies between logk'(IAM), physicochemical descriptors and P(a) were conducted by stepwise multiple linear regression (MLR) and back-propagation neural network (BPNN). MLR and BPNN showed that logk'(IAM) was the descriptor which correlated best with P(a). Considering the molar volume as an additional descriptor, the correlation was improved. Retention indices on IAM and the molar volume can be used concurrently to predict passive drug absorption.

Genomic and functional changes induced by the activation of the peripheral cannabinoid receptor CB2 in the promyelocytic cells HL-60. Possible involvement of the CB2 receptor in cell differentiation.

The function of the peripheral cannabinoid receptor (CB2), which is mainly expressed on hematopoietic cells, remains an enigma. In an attempt to decipher its role, we used Affymetrix DNA chips to investigate the gene expression profile of the promyelocytic cells HL-60 transfected with the CB2 receptor and activated with the cannabinoid agonist CP 55,940. Agonist exposure of these cells led to an activation of a mitogen-activated protein kinase cascade and a receptor desensitization, indicating a functional coupling of the transfected receptors. At the genomic level, activation of the CB2 receptors induced an up-regulation of nine genes involved in cytokine synthesis, regulation of transcription, and cell differentiation. A majority of them are under the control of the transcription factor NF-kappaB, whose nuclear translocation was demonstrated. Many features of the transcriptional events, reported here for the first time, appeared to be related to an activation of a cell differentiation program, suggesting that CB2 receptors could play a role in the initialization of cell maturation. Moreover, we showed that CB2-activated wild-type HL-60 cells developed properties usually found in host defense effector cells such as an enhanced release of chemotactic cytokines and an increased motility, characteristic of more mature cells of the granulocytic-monocytic lineage.