Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0847097 (acidity)
 15,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pactimibe sulfate is a novel acyl coenzyme A:cholesterol acyltransferase inhibitor. We conducted metabolic studies of pactimibe and its plasma metabolite, R-125528. Pactimibe had multiple metabolic pathways including indolin oxidation to form R-125528, omega-1 oxidation, N-dealkylation, and glucuronidation. Among them, the indolin oxidation and the omega-1 oxidation were dominant and were mainly catalyzed by CYP3A4 and CYP2D6, respectively. The intrinsic clearance (CL(int)) values for these pathways in human hepatic microsomes were 0.63 and 0.76 microl/min/mg-protein, respectively. On the other hand, the metabolic reaction for R-125528 was restricted. It was demonstrated that omega-1 oxidation was the only pathway that could eliminate R-125528 from the systemic circulation. To our surprise, only CYP2D6-expressing microsomes could catalyze the reaction, and omega-1 oxidation was strongly correlated with the CYP2D6 marker reaction, dextromethorphan O-demethylation (r(2) = 0.90), in human hepatic microsomes. Although R-125528 is an atypical substrate for CYP2D6 because of its acidity, the K(m) value was 1.8 microM for the reaction in human hepatic microsomes and the CL(int) value was as high as 75.0 microl/min/mg-protein. These results suggested that the systemic clearance of R-125528 was highly dependent on CYP2D6 activity and that several studies with CYP2D6 including drug-drug interaction and polymorphism sensitivity should be performed during development from the viewpoint of metabolite safety assessment. The finding that R-125528, an acidic compound devoid of basic nitrogen, was a good substrate for CYP2D6 raised a question about previously reported CYP2D6 models based on a critical electrostatic interaction with Asp(301) and/or Glu(216).
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PMID:CYP2D6-Mediated metabolism of a novel acyl coenzyme A:cholesterol acyltransferase inhibitor, pactimibe, and its unique plasma metabolite, R-125528. 1805 54

Pactimibe sulfate is a novel acyl coenzyme A:cholesterol acyltransferase inhibitor developed for the treatment of hypercholesterolemia and atherosclerotic diseases. Pactimibe has two equally dominant clearance pathways forming R-125528 by CYP3A4 and M-1 by CYP2D6 in vitro. R-125528 is a plasma metabolite and is cleared solely by CYP2D6 despite its acidity. To evaluate contributions of the cytochrome P450 enzymes on the pharmacokinetics of pactimibe and R-125528 in humans, drug-drug interaction studies using ketoconazole and quinidine were conducted. Eighteen healthy male subjects were given a single dose of pactimibe sulfate without and with 400 mg of ketoconazole (q.d.). With the concomitant treatment, the area under the plasma concentration-time curve (AUC(0-inf)) of pactimibe modestly increased 1.7-fold and AUC(0-tz) of R-125528 decreased by 55%. In addition, 17 healthy male subjects were given a single dose of pactimibe sulfate without and with 600 mg of quinidine (b.i.d.). With the concomitant treatment, the AUC(0-inf) for pactimibe modestly increased 1.7-fold. On the other hand, the AUC(0-tz) of R-125528 was markedly elevated 5.0-fold, although the AUC(0-inf) could not be adequately defined because the terminal elimination phase of R-125528 was not obtained in the study period up to 72 h. As the f(m CYP3A4) and f(m CYP2D6) values of pactimibe estimated from in vitro studies were 0.40 and 0.33, respectively, AUC increase ratios of pactimibe were estimated to be 1.7 with ketoconazole and 1.5 with quinidine. These values were well in accordance with the values observed in this study. Moreover, the f(m CYP2D6) of R-125528 estimated to be almost 1 would well explain the accumulation of R-125528 observed with the quinidine treatment.
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PMID:Effects of ketoconazole and quinidine on pharmacokinetics of pactimibe and its plasma metabolite, R-125528, in humans. 1844 69

Three dimensional pharmacophoric maps were generated for each isoforms of CYP2C9, CYP2D6 and CYP3A4 separately using independent training sets consist of highly potent substrates (seven substrates for each isoform). HipHop module of CATALYST software was used in the generation of pharmacophore models. The best pharmacophore model was chosen out of the several models on the basis of (i) highest ranking score, (ii) better fit value among training set, (iii) capability to screen substrates from data set and (iv) efficiency to identify the isoform specificity. The individual pharmacophore models (CYP2C9-hypo1, CYP2D6-hypo1 and CYP3A4-hypo1) are characterized by the pharmacophoric features XZDH, RPZH and XYZHH for the CYP2C9, CYP2D6 and CYP3A4 respectively. Each of the chosen models was validated by using data sets of CYP substrates. This comparative study of CYP substrates demonstrates the importance of acidic character along with HBD and HBAl features for CYP2C9, basic character with ring aromatic features for CYP2D6 and hydrophobic features for CYP3A4. Acidity, basicity and hydrophobicity features arising from the functional groups of the substrates are also responsible for demonstrating CYP isoform specificity. Hence, these chemical features are incorporated in the decision tree along with pharmacophore maps. Finally, a decision tree based on chemical features and pharmacophore features was generated to identify the isoform specificity of novel query molecule toward the three isoforms.
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PMID:CYP isoform specificity toward drug metabolism: analysis using common feature hypothesis. 2156 23