کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2487237 | 1114409 | 2009 | 13 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Factors that restrict intestinal cell permeation of cyclic prodrugs of an opioid peptide (DADLE): Part II. Role of metabolic enzymes in the intestinal mucosa
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کلمات کلیدی
P-glycoprotein - P-گلیکوپروتئینEsterase - استرسEfflux transporter - انتقال دهنده خروجیPeptide delivery - تحویل پپتیدOral absorption - جذب دهانیsulfotransferase - سولفوترانسفرازCytochrome P450 - سیتوکروم پی۴۵۰Intestinal mucosa - مخاط رودهProdrugs - پیش داروGlucuronyltransferase - گلوکورونیل ترانسفراز
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
پیش نمایش صفحه اول مقاله

چکیده انگلیسی
The objective of this study was to determine the relative importance of metabolism by cytochrome P450 (CYP) enzymes versus efflux by P-glycoprotein (P-gp) in restricting the intestinal mucosal permeation of cyclic prodrugs (AOA-DADLE, CA-DADLE, OMCA-DADLE) of the opioid peptide DADLE (H-Tyr-d-Ala-Gly-Phe-d-Leu-OH). AOA-DADLE, CA-DADLE, and OMCA-DADLE were shown to be rapidly metabolized by rat liver microsomes and human CYP-3A4 and to a lesser extent by esterases. Using an in situ perfused rat ileum model, ketoconazole, a CYP 3A inhibitor, was shown to have no effect (AOA-DADLE) or a slight enhancing effect (OMCA-DADLE, twofold; CA-DADLE, threefold) on their intestinal mucosal permeation. In contrast, inclusion of PSC-833, a P-gp inhibitor, in the perfusate significantly enhanced (7-16-fold) the permeation of the three cyclic prodrugs. Since PSC-833 was found to be a weak inhibitor of CYP 3A4 and to have no inhibitory effects on esterases, phenol sulfotransferases, and glucuronyltransferases, it is suggested PSC-833 enhances intestinal mucosal permeation of these cyclic prodrugs by inhibiting their polarized efflux and not by inhibiting their metabolism. Furthermore, efflux transporters (e.g., P-gp), not metabolic enzymes (e.g., CYP 3A, esterases), restrict the permeation of peptide prodrugs across the rat intestinal mucosa.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 98, Issue 1, January 2009, Pages 349-361
Journal: Journal of Pharmaceutical Sciences - Volume 98, Issue 1, January 2009, Pages 349-361
نویسندگان
Hui Ouyang, Weiqing Chen, Thomas E. Andersen, Bente Steffansen, Ronald T. Borchardt, Hui Ouyang, Weiqing Chen,