Significance of Reductive Metabolism in Human Intestine and Quantitative Prediction of Intestinal First-Pass Metabolism by Cytosolic Reductive Enzymes

Abstract

The number of new drug candidates that are cleared via noncytochrome P450 (P450) enzymes has increased. However, unlike oxidation by P450, the roles of reductive enzymes are less understood. The metabolism in intestine is especially not well known. The purposes of this study were to investigate the significance of reductive metabolism in human intestine, and to establish a quantitative prediction method of intestinal first-pass metabolism by cytosolic reductive enzymes, using haloperidol, mebendazole, and ziprasidone. First, we estimated the metabolic activities for these compounds in intestine and liver using subcellular fractions. Metabolic activities were detected in human intestinal cytosol (HIC) for all three compounds, and the intrinsic clearance values were higher than those in human liver cytosol for haloperidol and mebendazole. These metabolic activities in HIC were NADPH-and/or NADH-dependent. Furthermore, the metabolic activities for all three compounds in HIC were largely inhibited by menadione, which has been used as a carbonyl reductase (CBR)-selective chemical inhibitor. Therefore, considering subcellular location, cofactor requirement, and chemical inhibition, these compounds might be metabolized by CBRs in human intestine. Subsequently, we tried to quantitatively predict intestinal availability (F g ) for these compounds using human intestinal S9 (HIS9). Our prediction model using apparent permeability of parallel artificial membrane permeability assay and metabolic activities in HIS9 could predict F g in humans for the three compounds well. In conclusion, CBRs might have higher metabolic activities in human intestine than in human liver. Furthermore, our prediction method of human F g using HIS9 is applicable to substrates of cytosolic reductive enzymes.

Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol

“…[113] If given orally, it has a bioavailability of 60-70% due to first-pass metabolism. [112,114,115] For the subcutaneous route, there is no information available but bioavailability is probably around 100% as it diffuses from the subcutaneous tissue directly to the systemic circulation. Haloperidol is a lipophilic drug, and it is bound to albumin for more than 90%.…”

In Vitro and In Vivo Drug Interaction Study of Two Lead Combinations, Oxantel Pamoate plus Albendazole and Albendazole plus Mebendazole, for the Treatment of Soil-Transmitted Helminthiasis

“…The enzymes responsible for mebendazole metabolism have not been identified (17). However, in vitro tests have suggested involvement of CYPs (17) and the carbonyl transferase in the biotransformation of mebendazole (18). Finally, the absorption of oxantel pamoate is only 6 to 8% (19).…”

Physiologically‐based pharmacokinetics of ziprasidone in pregnant women

“…The effective permeability (P eff,man ) was estimated using data obtained from an in vitro permeability study in Caco‐2 cells, which consisted of 36 different compound standards of high (eg propranolol) and low (eg cimetidine) permeability . The fraction absorbed (f a ) was set to 0.90, the first‐order absorption rate constant (k a ) was set to 0.32 h −1 , fraction unbound in the gut (f ugut ) was set to 0.35 to match the gut availability (F g ) of 0.85, and the flow rate for overall delivery of drug to the gut (Q gut ) was 9.01 L h −1 , which was predicted by the system. The lag time was adjusted in the range of 2–3 h: for lower doses (5–20 mg) it was set to 2 h, and for higher doses (40–80 mg) it was set to 3 h. The rationale for this adjustment is that ZIP is poorly water‐soluble (free‐base solubility in pH 6.5 buffered media <0.1 mg/mL), classified as a class II (low solubility, high permeability) drug according to the biopharmaceuticals classification system (BCS).…”