It is a substrate of CYP 3A4 and inhibitor of CYP 2C9, CYP 2D6 and CYP 3A4. Apparently relatively weak reversible and irreversible inhibitor of CYP 3A4, with therapeutic plasma concentrations far below those needed for significant CYP-destruction. Observed to have been tolerated by 10 carriers of acute porphyria( per February 2010). Effect on PXR-activation of plasma calcium-deficit induced hypo-insulinemia cannot be excluded, but seems to be very rare and is e.g. under amlodipine treatment seemingly without clinical significance with regard to porphyrogenic ALAS1 induction.

Ethyl methyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate. M= 384. Dihydropyridine derivative, insoluble in water. Contains one cyclic tertiary amine group, shown in other drugs to cause irreversible or quasi-irreversible (nicardipine) inhibition (Ma, 2000; Hollenberg, 2008). Other cyclic tertiary amine MB-inhibitors have been shown to give rise to 2,3 dihydropyridinium metabolites, which bind to the CYP-apoprotein without loss of spectrally detectable heme (Hollenberg, 2008).

Felodipine is a dihydropyridine calcium-channel blocker with actions similar to those of nifedipine. It is used in the management of hypertension and angina pectoris. Felodipine exerts its effect by relaxing arterial and arteriolar smooth muscle. Common side effects that mimic porphyria symptoms are nausea, abdominal pain, paraethesia.

Possibly significant.

Weak reversible inibitor of CYP 2D6, CYP 2C9 and CYP 3A4 (Rendic, 2002; Katoh, 2000). It is a substrate and seemingly relatively weak irreversible inhibitor (Ki 13 uM) in vitro of CYP 3A4, attacking the protein component of the enzyme. Also inhibitor of P-gp, enhancing exposure. (Zhou, 2007). Therapeutic plasma concentrations are in the range 0,1-0,4 uM (Zhou, 2007), i.e a potency below the concentration needed for halfmaximal inhibition. The figure for the rate constant Kinact is not available, and thus the inactivation rate (Kobs) can not be calculated. It is a long-term drug treatment, which means long-term exposure of the drug, and thus potentially enhancing effects of possible low-intensity heme drain.

C.Andersson 2004; 3 patient reports in carriers of AIP. S.Thunell 2004; 2 patient reports in carriers of AIP.

Uneventful use reported in 10 patients with acute porphyria. One report of an acute attack of porphyria in a susceptable AIP male, but the report is poorly documented, and several other factors could explain the symptoms. This report has therefore not been taken into account in the judgement of the porphyrinogenicity of felodipine.