D01BA02 - Terbinafine |
Propably not porphyrinogenic |
PNP |
Rationale
Terbinafine is not an inducer or inhibitor of CYP3A4 and other major CYP enzymes in vivo.Risk for gastrointestinal adverse events in the form of abdominal distension, reduced appetite, nausea, dyspepsia, mild abdominal pain and diarrhoea motivates vigilance against insufficient intake of food, especially of carbohydrate.
Chemical description
Dimethylhept-e-yn (methyl)- (naphtyl methyl)- amine M=291.
Therapeutic characteristics
Terbinafine is indicated for the treatment of fungal infections of the skin and nails.
Very common side effects that can be potentially porphyrinogenic through reduction in carbohydrate intake and that also can be confused with an acute porphyria attack are abdominal distension, reduced appetite, nausea, dyspepsia, mild abdominal pain and diarrhoea. Other common side effects are arthralgia and myalgia.
Metabolism and pharmakokinetics
Terbinafine is metabolized by CYP2C9, CYP1A2, CYP3A4, CYP2C8 and CYP2C19. The half-life elimination is between 17-400 hours (Castberg 2005).
In vitro and in vivo data indicates that terbinafine is a competitive inhibitor of CYP2D6 (Castberg 2005 and Vickers 1999).
In vitro studies have shown that terbinafine had little or no effect on theophylline (CYP1A2), tolbutamine (CYP2C9), (S)-mephenytoin (CYP2C19) and cyclosporine A (CYP3A). The potential for drug-drug interactions with CYP1A2, CYP2C9, CYP2C19 and CYP3A is predicted to be insignificant (Vickers 1999).
A clinical study showed that co-administration of terbinafine and midazolam, a CYP3A4 substrate, did not decrease the AUC of midazolam significantly (Ahonen 1995). This indicates that terbinafine is not an inhibitor or an inducer of CYP3A4.
While a clinical study showed that the AUC of cyclosporine (CYP3A substrate) decreased by 12.9% when co-administered with terbinafine (Long 1994), another showed that co-administration of terbinafine and theophylline (CYP3A4 substrate) resulted in an increase of the AUC by 16% (Trépanier 1998). Both the decrease and increase in AUC is however, according to the U.S Food and Drug Administration, too low for terbinafine to be considered as an inducer or an inhibitor (FDA).
References
- Scientific articles
- Ahonen J, Olkkola KT, Neuvonen PJ. Effect of itraconazole and terbinafine on the pharmacokinetics and pharmacodynamics of midazolam in healthy volunteers. Br J Clin Pharmacol. 1995 Sep;40(3):270-2. PMID 8527290. #1347
- Castberg I, Helle J, Aamo TO. Prolonged pharmacokinetic drug interaction between terbinafine and amitriptyline. Ther Drug Monit. 2005 Oct;27(5):680-2. PMID 16175144. #1348
- Cui X, Thomas A, et al. Application and interpretation of hPXR screening data: Validation of reporter signal requirements for prediction of clinically relevant CYP3A4 inducers. Biochem Pharmacol. 2008 Sep 1;76(5):680-9. PMID 18647599. #4344
- Fahmi OA, Kish M, et al. Cytochrome P450 3A4 mRNA is a more reliable marker than CYP3A4 activity for detecting pregnane X receptor-activated induction of drug-metabolizing enzymes. Drug Metab Dispos. 2010 Sep;38(9):1605-11. PMID 20566695. #4426
- Trépanier EF, Nafziger AN, Amsden GW. Effect of terbinafine on theophylline pharmacokinetics in healthy volunteers. Antimicrob Agents Chemother. 1998 Mar;42(3):695-7. PMID 9517954. #1350
- Vickers AE, Sinclair JR, et al. Multiple cytochrome P-450s involved in the metabolism of terbinafine suggest a limited potential for drug-drug interactions. Drug Metab Dispos. 1999 Sep;27(9):1029-38. #1352
- Drug reference publications
- Up to date. cyclosporine, midazolam, terbinafine, theophylline #1351
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