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Pathway Description
Voriconazole Metabolism
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Metabolic
Created: 2022-06-17
Last Updated: 2023-10-25
Voriconazole is an triazole antifungal medication used to treat serious, invasive fungal infections. It has increased affinity to 14-alpha sterol demethylase which means it is useful against Fluconazole-resistant organisms. Voriconazole is taken either orally or injected intravenously. The bioavailability of voriconazole is 96%. When taken orally it is transported from the intestine into the intestinal epithelial cell possibly via solute carrier family 15 member 1, one of 3 drug transporters into epithelial cells. It is then transported into blood vessels via ATP-binding cassette sub-family C member 3. It is then transported through the blood to the liver where it is transported in by a liver drug transporter like solute carrier family 22 member 1.
On the endoplasmic reticulum membrane Voriconazole is metabolized into Voriconazole N-Oxide by Cytochrome P450 2C9, Cytochrome P450 2C19, Cytochrome P450 3A4, Cytochrome P450 3A5, or Cytochrome P450 3A7, which makes up 72% of metabolites found. Voriconazole N-Oxide is metabolized into a voriconazole related compound (UK-51,060) by an unknown enzyme. That is predicted by biotransformer to be metabolized by Carbonyl reductase [NADPH] 1 into a similar voriconazole related compound (UK-215,364). That is predicted by biotransformer to be metabolized by UDP-glucuronosyltransferase 1-3 into Voriconazole O-glucuronide derivative (1).
Voriconazole also metabolizes into 4-Hydroxyvoriconazole via the enzymes Cytochrome P450 3A4, Cytochrome P450 3A5, or Cytochrome P450 3A7. 4-Hydroxyvoriconazole is predicted by biotransformer to be metabolized by UDP-glucuronosyltransferase 1-3 into 4-Hydroxyvoriconazole 4-O-glucuronide.
Voriconazole and all the metabolites are transported out of the liver and into blood vessels by a transport protein such as multidrug resistance-associated protein 4. They all then travel to the kidney where they are excreted in the urine. Less than 2% of the dose is excreted as unchanged voriconazole. 72% is excreted as the metabolite voriconazole N-oxide.
References
Voriconazole Metabolism References
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Pubmed: 17344335
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Forrest GL, Akman S, Krutzik S, Paxton RJ, Sparkes RS, Doroshow J, Felsted RL, Glover CJ, Mohandas T, Bachur NR: Induction of a human carbonyl reductase gene located on chromosome 21. Biochim Biophys Acta. 1990 Apr 6;1048(2-3):149-55. doi: 10.1016/0167-4781(90)90050-c.
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Sakata T, Anzai N, Shin HJ, Noshiro R, Hirata T, Yokoyama H, Kanai Y, Endou H: Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions. Biochem Biophys Res Commun. 2004 Jan 16;313(3):789-93. doi: 10.1016/j.bbrc.2003.11.175.
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Janke D, Mehralivand S, Strand D, Godtel-Armbrust U, Habermeier A, Gradhand U, Fischer C, Toliat MR, Fritz P, Zanger UM, Schwab M, Fromm MF, Nurnberg P, Wojnowski L, Closs EI, Lang T: 6-mercaptopurine and 9-(2-phosphonyl-methoxyethyl) adenine (PMEA) transport altered by two missense mutations in the drug transporter gene ABCC4. Hum Mutat. 2008 May;29(5):659-69. doi: 10.1002/humu.20694.
Pubmed: 18300232
Lee K, Belinsky MG, Bell DW, Testa JR, Kruh GD: Isolation of MOAT-B, a widely expressed multidrug resistance-associated protein/canalicular multispecific organic anion transporter-related transporter. Cancer Res. 1998 Jul 1;58(13):2741-7.
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Pubmed: 12105214
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