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Pathway Description
Nevirapine Metabolism Pathway
Homo sapiens
Drug Metabolism Pathway
Created: 2013-09-11
Last Updated: 2019-09-12
Nevirapine is used in the treatment of human immunodeficiency virus (HIV) type 1 (HIV-1) infection. It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that binds to the tyrosines at amino acid residues 181 and 188 of HIV-1 reverse transcriptase. Nevirapine is metabolized in the liver to 2-, 3-, 8-, and 12-hydroxynevirapine by the induction of CYP enzymes, mainly CYP3A4 and CYP2B6. 12-hydroxynevirapine may be further oxidated by ALDH to form 4-carboxynevirapine. These hydroxyl metabolites are glucuronidated by UDP glucuronosyl transferases (UGTs), then exit the cell via the adenosine triphosphate-binding cassette gene ABCC10 for urinary excretion.
References
Nevirapine Pathway References
[PharmgKB](http://www.pharmgkb.org/pathway/PA165950411)
Wen B, Chen Y, Fitch WL: Metabolic activation of nevirapine in human liver microsomes: dehydrogenation and inactivation of cytochrome P450 3A4. Drug Metab Dispos. 2009 Jul;37(7):1557-62. doi: 10.1124/dmd.108.024851. Epub 2009 Apr 13.
Pubmed: 19364830
Chen J, Mannargudi BM, Xu L, Uetrecht J: Demonstration of the metabolic pathway responsible for nevirapine-induced skin rash. Chem Res Toxicol. 2008 Sep;21(9):1862-70. doi: 10.1021/tx800177k. Epub 2008 Aug 26.
Pubmed: 18729332
Riska P, Lamson M, MacGregor T, Sabo J, Hattox S, Pav J, Keirns J: Disposition and biotransformation of the antiretroviral drug nevirapine in humans. Drug Metab Dispos. 1999 Aug;27(8):895-901.
Pubmed: 10421616
Liptrott NJ, Pushpakom S, Wyen C, Fatkenheuer G, Hoffmann C, Mauss S, Knechten H, Brockmeyer NH, Hopper-Borge E, Siccardi M, Back DJ, Khoo SH, Pirmohamed M, Owen A: Association of ABCC10 polymorphisms with nevirapine plasma concentrations in the German Competence Network for HIV/AIDS. Pharmacogenet Genomics. 2012 Jan;22(1):10-9. doi: 10.1097/FPC.0b013e32834dd82e.
Pubmed: 22082652
Cheeseman SH, Hattox SE, McLaughlin MM, Koup RA, Andrews C, Bova CA, Pav JW, Roy T, Sullivan JL, Keirns JJ: Pharmacokinetics of nevirapine: initial single-rising-dose study in humans. Antimicrob Agents Chemother. 1993 Feb;37(2):178-82.
Pubmed: 8452345
Havlir D, Cheeseman SH, McLaughlin M, Murphy R, Erice A, Spector SA, Greenough TC, Sullivan JL, Hall D, Myers M, et al.: High-dose nevirapine: safety, pharmacokinetics, and antiviral effect in patients with human immunodeficiency virus infection. J Infect Dis. 1995 Mar;171(3):537-45.
Pubmed: 7533197
Chen ZS, Hopper-Borge E, Belinsky MG, Shchaveleva I, Kotova E, Kruh GD: Characterization of the transport properties of human multidrug resistance protein 7 (MRP7, ABCC10). Mol Pharmacol. 2003 Feb;63(2):351-8. doi: 10.1124/mol.63.2.351.
Pubmed: 12527806
Kao HH, Chang MS, Cheng JF, Huang JD: Genomic structure, gene expression, and promoter analysis of human multidrug resistance-associated protein 7. J Biomed Sci. 2003 Jan-Feb;10(1):98-110. doi: 10.1007/bf02256002.
Pubmed: 12566991
Hattori A, Okumura K, Nagase T, Kikuno R, Hirosawa M, Ohara O: Characterization of long cDNA clones from human adult spleen. DNA Res. 2000 Dec 31;7(6):357-66. doi: 10.1093/dnares/7.6.357.
Pubmed: 11214971
Lang T, Klein K, Fischer J, Nussler AK, Neuhaus P, Hofmann U, Eichelbaum M, Schwab M, Zanger UM: Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics. 2001 Jul;11(5):399-415.
Pubmed: 11470993
Lang T, Klein K, Richter T, Zibat A, Kerb R, Eichelbaum M, Schwab M, Zanger UM: Multiple novel nonsynonymous CYP2B6 gene polymorphisms in Caucasians: demonstration of phenotypic null alleles. J Pharmacol Exp Ther. 2004 Oct;311(1):34-43. doi: 10.1124/jpet.104.068973. Epub 2004 Jun 9.
Pubmed: 15190123
Yamano S, Nhamburo PT, Aoyama T, Meyer UA, Inaba T, Kalow W, Gelboin HV, McBride OW, Gonzalez FJ: cDNA cloning and sequence and cDNA-directed expression of human P450 IIB1: identification of a normal and two variant cDNAs derived from the CYP2B locus on chromosome 19 and differential expression of the IIB mRNAs in human liver. Biochemistry. 1989 Sep 5;28(18):7340-8. doi: 10.1021/bi00444a029.
Pubmed: 2573390
Hsieh KP, Lin YY, Cheng CL, Lai ML, Lin MS, Siest JP, Huang JD: Novel mutations of CYP3A4 in Chinese. Drug Metab Dispos. 2001 Mar;29(3):268-73.
Pubmed: 11181494
Molowa DT, Schuetz EG, Wrighton SA, Watkins PB, Kremers P, Mendez-Picon G, Parker GA, Guzelian PS: Complete cDNA sequence of a cytochrome P-450 inducible by glucocorticoids in human liver. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5311-5. doi: 10.1073/pnas.83.14.5311.
Pubmed: 3460094
Gonzalez FJ, Schmid BJ, Umeno M, Mcbride OW, Hardwick JP, Meyer UA, Gelboin HV, Idle JR: Human P450PCN1: sequence, chromosome localization, and direct evidence through cDNA expression that P450PCN1 is nifedipine oxidase. DNA. 1988 Mar;7(2):79-86. doi: 10.1089/dna.1988.7.79.
Pubmed: 3267210
Kimura S, Umeno M, Skoda RC, Meyer UA, Gonzalez FJ: The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am J Hum Genet. 1989 Dec;45(6):889-904.
Pubmed: 2574001
Gaedigk A, Bhathena A, Ndjountche L, Pearce RE, Abdel-Rahman SM, Alander SW, Bradford LD, Rogan PK, Leeder JS: Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans. Pharmacogenomics J. 2005;5(3):173-82. doi: 10.1038/sj.tpj.6500305.
Pubmed: 15768052
Sridar C, Snider NT, Hollenberg PF: Anandamide oxidation by wild-type and polymorphically expressed CYP2B6 and CYP2D6. Drug Metab Dispos. 2011 May;39(5):782-8. doi: 10.1124/dmd.110.036707. Epub 2011 Feb 2.
Pubmed: 21289075
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