Detail The role of the kidney in human toxicology: P-glycoprotein-mediated drug interactions and intrarenal drug metabolism Bibliografi Author: Woodland, Cindy Lisa Patricia ; Koren, Gideon (Advisor); Ito, Shinya (Advisor) Topik: HEALTH SCIENCES; PHARMACOLOGY|HEALTH SCIENCES; TOXICOLOGY Bahasa: (EN )    ISBN: 0-612-49967-7     Penerbit: UNIVERSITY OF TORONTO     Tahun Terbit: 2000     Jenis: Theses - Dissertation Fulltext: NQ49967.pdf (0.0B; 1 download) Abstract The prime role of the kidney in drug elimination makes it a target for drug-induced toxicity. Using a renal tubular cell culture model that allows separation of the apical and basolateral compartments, I studied the renal tubular handling of substrates of the P-glycoprotein drug transporter. This thesis will highlight the importance of renal tubular drug interactions to systemic toxicity. The cardiac glycoside digoxin was used as an example drug because its low therapeutic index necessitates an understanding of its renal elimination in the presence of interacting drugs. The in vitro model allowed me to characterize known digoxin-drug interactions with propafenone and verapamil and to identify potential digoxin-drug interactions with mifepristone and itraconazole. Metabolites of propafenone and verapamil were found to contribute to the interactions with digoxin. Moreover, the renal tubular cells were capable of biotransforming propafenone and verapamil to their major metabolites. The importance of renal drug biotransformation to human toxicity is illustrated with the chemotherapeutic agent ifosfamide. Nephrotoxicity is often a limiting factor in the use of ifosfamide in children. Despite the co-administration of the uroprotective agent mesna (sodium 2-mercaptoethane sulfonate), ifosfamide chemotherapy is associated with nephropathy characterized by glomerular and tubular toxicity consistent with the Fanconi syndrome. This is in distinction to cyclophosphamide, an analogue which differs solely by the position of a chloroethyl group, that is not associated with nephrotoxicity. The major nephrotoxic metabolites of ifosfamide have short half-lives and it is difficult to model renal damage caused by them after production by the liver. I hypothesized that ifosfamide is metabolized by CYP enzymes located in the renal tubular cell to the toxic metabolite chloroacetaldehyde. My results show that porcine and human kidney microsomes are capable of biotransforming ifosfamide to dechloroethylifosfamide metabolites, indicating that local production of chloroacetaldehyde in the renal tubular cell is a possible mechanism for nephrotoxicity. Opini Anda Klik untuk menuliskan opini Anda tentang koleksi ini! Lihat Sejarah Pengadaan  Konversi Metadata   Kembali

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