Publications (5) View all
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Article: Investigation of drug-drug interaction via mechanism-based inhibition of cytochrome P450 3A by macrolides in dexamethasone-treated female rats.
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ABSTRACT: The in vitro and in vivo inhibition of cytochrome P450 (CYP) 3A with mechanism-based inhibition (MBI) by macrolides was investigated using dexamethasone-treated female rats (DEX-female rats). In the in vitro CYP inhibition studies using erythromycin (ERM) and clarithromycin (CAM), similar inhibition responses were observed between human and DEX-female rat liver microsomes, however, there were fewer effects in intact male rats. The ex vivo study showed that midazolam (MDZ) metabolism in liver microsomes of DEX-female rats was reduced by ERM administration and the inhibitory effect was increased with increasing ERM doses, indicating that metabolite intermediate complex formation caused irreversible inhibition of CYP3A activity in DEX-female rats as well as in humans. In the in vivo studies, ERM and CAM significantly increased the area under the plasma concentration-time curve of MDZ and decreased the total clearance in DEX-female rats. It was concluded that the DDIs via MBI of CYP3A following macrolide administration in humans could be reproduced in female rats, suggesting that DEX-female rats can serve as an in vivo model for assessing this DDI in humans.Biopharmaceutics & Drug Disposition 03/2012; 33(4):195-206. · 2.07 Impact Factor -
Article: 2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists. Part 2: orally bioavailable compounds.
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ABSTRACT: Structure-activity relationships and efforts to optimize the pharmacokinetic profile of a class of 2-arylimino-5,6-dihydro-4H-1,3-thiazines as cannabinoid receptor agonists are described. Among the compounds examined, compound 14 showed potent affinity and high selectivity for CB2, and compound 23 showed potent affinities against CB1 and CB2. These compounds displayed oral bioavailability.Bioorganic & Medicinal Chemistry Letters 08/2007; 17(14):3925-9. · 2.55 Impact Factor -
Article: Assessment of the hepatic and intestinal first-pass metabolism of midazolam in a CYP3A drug-drug interaction model rats.
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ABSTRACT: In the current study, to understand the characteristics of dexamethasone (DEX)-treated female rats as an animal model for drug-drug interactions, a double-cannulation method was applied and separately assessed for the intestinal and hepatic first-pass metabolism of midazolam. Midazolam was administered intravenously or orally to the animals, and midazolam concentrations in the portal and systemic plasma were simultaneously determined. Next, the rates of elimination from the intestine and liver were estimated using the AUC values. After oral administration of midazolam, the entire drug was absorbed without intestinal first-pass metabolism, and 93% of the administered midazolam was extracted in the liver of the DEX-treated female rats. Seven per cent of the midazolam administered reached the systemic circulation. When ketoconazole was given orally to the animals, in conjunction with midazolam, the extraction ratio in the liver decreased from 93% to 77% in the control rats, and the bioavailability of midazolam increased to 23%. On the other hand, after intravenous administration, the elimination half-life of midazolam was not changed by ketoconazole pretreatment. These results indicated that midazolam is only extracted in the liver of DEX-treated female rats and that ketoconazole inhibits the hepatic first-pass metabolism, but not the systemic metabolism. In conclusion, DEX-treated female rats can be used as a drug-drug interaction model via CYP3A4 enzyme inhibition, especially for the hepatic first-pass metabolism of orally administered drugs.Xenobiotica 05/2005; 35(4):305-17. · 1.79 Impact Factor -
Article: Effects of serum albumin and liver cytosol on CYP2C9- and CYP3A4-mediated drug metabolism.
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ABSTRACT: To investigate whether the free-drug theory is accurate in that only unbound drug is available for drug metabolism or enzyme inhibition. The effect of addition of rat liver cytosol to an in vitro system using human liver microsomes was examined by measuring the catalytic activities of CYP2C9 (tolbutamide and diclofenac) and CYP3A4 (terfenadine). And, the results were compared with those obtained when human serum albumin (HSA) was added to microsomes as far as unbound drug concentrations were concerned. After addition of rat liver cytosol, the unbound Km value (Km,u) for terfenadine metabolism by CYP3A4, and the unbound Ki value of miconazole (Ki,u) for CYP2C9 were smaller than for the controls. Addition of HSA resulted in smaller Km,u values for diclofenac and terfenadine metabolism by CYP2C9 and CYP3A4, respectively, and the Ki,u value for ketoconazole inhibition of CYP3A4 was also reduced. These results suggest protein-facilitated effects on drug metabolism and enzyme inhibition for both CYP2C9 and CYP3A4. However, no protein-facilitated drug metabolism was observed for tolbutamide in the presence of HSA or cytosol, or for diclofenac in the presence of cytosol. Protein-facilitated enzyme inhibition did not occur with miconazole in the presence of HSA or with ketoconazole in the presence of rat liver cytosol. Protein-facilitated metabolism and enzyme inhibition were observed for CYP2C9 and CYP3A4 in five cases but there was no obvious pattern of enzyme, substrate, or binding protein specificity. Further investigations are necessary to clarify the relevance of these results to in vivo observations.Drug Metabolism and Pharmacokinetics 02/2002; 17(6):522-31. · 2.32 Impact Factor -
Article: Contribution of CYP4A8 to the formation of 20-hydroxyeicosatetraenoic acid from arachidonic acid in rat kidney.
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ABSTRACT: 20-Hydroxyeicosatetraenoic acid (20-HETE) has been shown to be an arachidonic acid metabolite of the cytochrome P450 (CYP) enzymes belonging to the CYP4A subfamily and is a predominant regulator of renal vascular tone and tubular ion reabsorption in rat kidney. CYP4A8 is one of the CYP4A enzymes expressed in rat kidney, but its contribution to 20-HETE formation has not been assessed. In order to clarify that the role of CYP4A8, we have developed bacterial expression systems for the expression of recombinant CYP4A8 (rCYP4A8). We also produced an antibody against rCYP4A8 which was used for immunoinhibition and immunohistochemical studies. In a reconstituted system, rCYP4A8 sufficiently catalyzed 20-HETE formation as well as prostaglandin A(1) omega-hydroxylation, a marker activity for CYP4A8. In addition, anti-rCYP4A8 sera significantly inhibited prostaglandin A(1) omega-hydroxylation and strongly inhibited arachidonic acid omega-hydroxylation in rat kidney microsomes. These observations suggested for the first time that CYP4A8 also contributed to 20-HETE formation in rat kidney. Furthermore, immunohistochemstry suggested that CYP4A8 is present in preglomerular arteries, where 20-HETE has been established to be a vasoconstrictor.Drug Metabolism and Pharmacokinetics 02/2002; 17(2):109-16. · 2.32 Impact Factor
