C09CA01 - Losartan |
Propably not porphyrinogenic |
PNP |
Rationale
Losartan is a substrate to CYP3A4, CYP2C9 and CYP2C10. No data is pointing to CYP induction or mechanism based inhibition, and losartan is therefore not suspected to be porphyrinogenic. This is also supported by 33 clinical observations of uneventful use of losartan.
Chemical description
Losartan is an angiotensin II receptor antagonist.
Therapeutic characteristics
Antihypertensive
Metabolism and pharmakokinetics
Losartan is a prodrug which is converted into its main active metabolite E3174, a carboxylic acid, by CYP3A4, CYP2C9 (Zaidenstein et al. 2001) and CYP2C10 (Sica et al. 2005). In vitro studies indicate that CYP2C9 is the major contributor while CYP3A4 oxidation is only significant at very high concentrations of losartan (Yasar et al. 2001). E3174 is 40 times more potent than losartan (Up to date 2013).
Losartan inhibits CYP1A2 (weak), CYP2C19 (weak), CYP2C8 (moderate), CYP2C9 (moderate) and CYP3A4 (weak) (Up to date 2013). In vitro studies state that losartan have modest affinity to CYP2C9 (Taavitsainen et al. 2000). No data is indicating that losartan is a mechanism based inhibitor.
Extensive first pass effect. Half-life elimination: Losartan: 1.5-2 hours; E-3174: 6-9 hours.
Personal communication
Thunell, patient report (n = 1): tolerated. Anderson, patient report (n = 2): tolerated.
IPNet drug reports
Uneventful use reported in 30 patients with acute porphyria.
References
- Scientific articles
- Sica D. A., Gehr T. W. B., Ghosh S. Clincial Pharmacokinetics of Losartan. Clinical Pharmacokinetics 2005;44(8):797-814. #1309
- Taavitsainen P. , Kiukaanniemi K., Pelkonen O. In vitro inhibition screening of human hepatic P450 enzymes by five angiotensin-II receptor antagonist. European Journal of Clinical Pharmacology 2000;56:135-140. PMID 10877007. #4412
- Yasar Ü. , Tybring M., Hidestrand M., Oscarson M., Ingelman-Sundberg., Dahl M., Eliasson E. Role of CYP2C9 Polymorphism in Losartan Oxidation. Drug metabolism and disposition 2001;29(7):1051-1056. PMID 11408373. #4413
- Zaidenstein R. , Soback, S., Gips, M., Avni, B., Dishi, V., Weissgarten, Y., Golik, A., Scapa, E. Effect of grapefruit juice on the pharmacokinetics of losartan and its active metabolite E3174 in healthy volunteers. Therapeutic Drug Monitoring 2001;23(4):369-373. PMID 11477318. #4414
- Drug reference publications
- Up to date. Losartan. #1311
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