Mucosal Biotransformation

Abstract

About 4 million compounds have been described by chemists, and some 60,000 are presently on the market. The search for new chemicals with better properties and less toxicity continues, and future life quality will depend on our ability to find the safest compounds in each field of application. During development of new drugs and chemicals, studies on biotransformation should be done very early, and with adequate analytical tools, in order to get an early understanding of data on bioavailability, metabolic pattern, and toxicity. Though the liver is generally the organ with the highest drug metabolizing activity, it becomes increasingly evident that some extrahepatic organs, such as intestine, kidney, skin, and lung also participate in drug metabolism. The peculiar property of intestinal metabolism is the fact that it modifies chemicals before they enter the circulation. Therefore, an understanding of intestinal metabolism is important for proper interpretation of all pharmacological and toxicological data during development of a new compound. Mucosal biotransformation has recently been reviewed. The present work gives a schematic survey on the topic, shows new trends, and discusses the consequences for toxicological testing of new chemicals.

Semiphysiologically Based Pharmacokinetic Models for the Inhibition of Midazolam Clearance by Diltiazem and Its Major Metabolite

“…The expression of cytochromes P450 in enterocytes results in significant presystemic intestinal metabolism of drugs and possible gut wall DDIs after oral administration (Schwenk, 1988;Kaminsky and Fasco, 1991;Paine and Oberlies, 2007). The results of the current clinical study showed that DTZ treatment led to a much higher AUC increase for oral MDZ (4.1-fold) than for intravenous MDZ (1.6-fold), suggesting that the interaction between DTZ and MDZ occurred mainly during the first pass for this low-extraction-ratio drug.…”

Prediction of CYP3A-Mediated Drug-Drug Interactions Using Human Hepatocytes Suspended in Human Plasma

“…It is well known that the expression of CYP3A enzymes in enterocytes results in significant presystemic intestinal metabolism of drugs and possible gut wall DDIs after oral administration (Schwenk, 1988;Kaminsky and Fasco, 1991;Paine and Oberlies, 2007). Clinical studies included in the dataset used in this investigation showed that ketoconazole, voriconazole, troleandomycin, erythromycin, clarithromycin, diltiazem, and conivaptan treatments led to a higher AUC increase for oral midazolam than for intravenous midazolam.…”

Intestinal Metabolism Promotes Regional Differences in Apical Uptake of Indinavir: Coupled Effect of P-Glycoprotein and Cytochrome P450 3A on Indinavir Membrane Permeability in Rat

“…Since CYP3A represents about 30 and 70% of total cytochrome P450 activity in liver and intestine, respectively (Watkins et al, 1987;de Waziers et al, 1990;Paine et al, 1997), first-pass metabolism is projected to play a significant role in poor and variable bioavailability of some drugs that are substrates for CYP3A (Back and Rogers, 1987;Schwenk, 1988). Intestinal first-pass metabolism mediated by CYP3A has been shown to be clinically relevant for several drugs such as cyclosporin A (Hebert et al, 1992;Wu et al, 1995), midazolam (Paine et al, 1996), and possibly other CYP3A substrates, including the HIV protease inhibitor, saquinavir (Fitzsimmons and Collins, 1997).…”