Lercanidipine: Although lercanidipine possesses a tertiary amin, a functional group that has been associated with MI-complex formation and mechanism-based inhibition of CYP enzymes in other substrates, lercanidipine has not been reported to be mechanism-based inhibitor of any CYP enzymes. Enalapril: No evidence of CYP-dependent metabolism. Older references indicate that an attack has been associated with enalapril, but newer clinical data question the causality of this observation. Porhyrin accumulation has been found in a model with primary chick embryo liver cells. These findings were at high supratherapeutic concentrations, and seem less relevant. The magnitude of uneventful clinical experience, including a small open study with 15 AIP patients, points to non-porphyrinogenicity. Risk for gastrointestinal adverse events in the form of nausea and diarrhoea motivates vigilance against insufficient intake of food, especially of carbohydrate.

Lercanidipine: Dihydropyridine calcium antagonist Enalapril: Derivative of the amino acid L-proline

Lercanidipine: Lercanidipine is used in the treatment of mild to moderate essential hypertension. It is administered orally. Enalapril: ACE-inhibitor. A very common side effect that can be potentially porphyrinogenic through reduction in carbohydrate intake and that also can be confused with an acute porphyria attack is nausea. Common side effects are diarrhoea, abdominal pain, tachycardia and fatigue.

Lercanidipine: Lercanidipine is extensively metabolized by CYP3A4 (Klotz 2002, SPC). In vitro studies with human liver microsomes have found lercanidipine to inhibit CYP3A4 and CYP2D6 (SPC). However, inhibition was found at concentrations 150-fold higher than the maximal plasma concentration after administration of doses of 20 mg. In vivo coadministration of lercanidipin and the CYP3A4 substrate simvastatin showed a 56 % and 28 % increase in the AUC of simvastatin and its active metabolite, respectively (Zhou 2013). According to the FDAs classification of inhibitors, lercanidipine may thus be described as a weak inhibitor of CYP3A4 in vivo (FDA). On the other hand lercanidipine did not alter the metabolism of the CYP3A4 substrate midazolam or the CYP2D6 substrate metoprolol, when coadministrated in vivo (McClellan 2000). Lercanidipine possesses a tertiary amine. Tertiary amines may undergo N-dealkylation resulting in a metabolic intermediate which has been shown in other drugs to cause mechanism-based inhibition of CYP enzymes (Riley 2007, Zhou 2007). Lercanidipine has not been reported to be a mechanism-based inhibitor of any CYP enzymes. Lercanidinpine is not listed as a mechanism-based inhibitor or an inducer (Hisaka 2010, Isoherranen 2009, Pelkonen 2008). Enalapril: Hydrolyzed to enalaprilate, otherwise not metabolized. CYP450 is not involved in the hydrolysis of enalapril.

Enalapril: Studies with primary chick embryo liver cells treated with desferrioxamine simulating conditions found in porphyric patients showed that enalapril substantially increased porphyrin accumulation when given in very high concentrations (Lambrecht RW et al. 1999). According to the authors patients with acute porphyrias may be at greater risk for developing porphyric attacks when treated with enalapril, compared to captopril or lisinopril. The therapeutic plasma concentrations of enalapril (as enalaprilate) are normally under 0.05 microgram/ml (0.13 microM). The concentrations at which Lambrecht et al found porphyrin accumulation in their experiment were more than 2000 times higher.

Enalapril: Andersson, patient report (n=6): tolerated.

Enalapril: Short term use of enalapril did not induce a clinical or biochemical attack in 15 AIP patients. This was demonstrated by clinical examination and unaltered Watson Schwartz test (12-hour for 72 hours after dosing), thus establishing its safety (Bandyopadhyay M et al, 2002). In a review article enalapril is listed as being associated with attacks (Gorchein A, 1997) while referring to the Oxford Textbook of Medicine, Third Edition, as well as to the British National Formulary. In subsequent editions of these sources the editors no longer list enalapril as a porphyrinogenic drug. Other sources like Martindale and the Australian webside most likely refer to the same observation(s). In the light of the findings of Bandyopadhyay et al the earlier observation(s) may lack causality.

Lercanidipine: Uneventful use reported in 1 patient with acute porphyria. Enalapril: Uneventful use reported in 44 patients with acute porphyria.