Amlodipine: Mechanism-based CYP 3A4-inhibitor, probably of too low potency to be porphyrogenic. No significant inhibition or induction of CYP 3A4 is observed in clinical use. One publication reports an acute attack following the use of amlodipine, but there are 37 reports (per January 2010) of safe use in carriers of acute porphyria. Dyspeptic symptoms may cause potentially porphyrogenic reductions in food intake. Effect on PXR-activation by plasma calcium-deficit hypo-insulinemia can not be excluded, but are reported to be rare, and seemingly without clinical significance with regard to porphyrogenic ALAS1-induction. Perindopril: Clinical experience and pharmacokinetic data points to non-porphyrinogenicity. Risk for gastrointestinal adverse events in the form of nausea, vomiting, abdominal pain, dyspepsia, diarrhoea and obstipation motivates vigilance against insufficient intake of food, especially of carbohydrate.

Amlodipine: 3-Ethyl 5-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate. M =408.9. Dihydropyridine derivative. 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). Perindopril: (2S,3aS,7aS)-1-{N-[(S)-1-Ethoxycarbonylbutyl]-l-alanyl}perhydroindole-2-carboxylic acid. M= 368.5

Amlodipine: Amlodipine is a dihydropyridine calcium-channel blocker. It is used in the management of hypertension and angina pectoris. Amlodipine exerts its effect by relaxing arterial and arteriolar smooth muscle. The common side effects are nausea, acute abdominal pain, dyspepsia and dyspnoea. Less common side effects are insomnia, irritability, depressive mode, back-pain, myalgia, arthalgia, paraesthesia and peripheral neuropathy. Perindopril: Perindopril is an angiotensin-converting enzyme (ACE) inhibitor used in hypertension, heart failure, and myocardial infarction. 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 nausea, vomiting, abdominal pain, dyspepsia, diarrhoea and obstipation.

Amlodipine: Possibly significant.

Amlodipine: Amlodipine is extensively metabolized in the liver by CYP 3A4. It is a substrate and only moderately potent (Ki=4.9 uM) inhibitor of CYP 3A4. It is not a substrate of P-Gp. Listed as irreversible CYP 3A4-inhibitor (kinact=0.35; Ki=2.6 uM; plasma concentration=0.1-0.4 uM. Partition ratio data not available)(Zhou, 2007). On CYP-oxidation the tertiary amine function undergoes N-dealkylation forming a reactive intermediate which attacks the heme-component of the enzyme (Hollenberg, 2008). The therapeutic plasma concentration of the drug in comparison to the relatively high concentration needed for half-maximal CYP 3A4- inhibition (Ki=2,6 uM)) makes it less likely for amlodipine to cause irrversible CYP-inhibition and heme-destruction of a degree to cause a significant ALAS1-induction. On the other hand it is used in long-term therapy, with a possible chronic low-intensive drain of hepatic heme. In clinical use, there are no observations of significant inibition or induction of CYP-metabolism of other drugs (Nishio, 2005; Meredith, 1992). Perindopril: The prodrug perindopril is extensively metabolised, mainly in the liver, to the active perindoprilat and inactive metabolites including glucuronides. Perindoprilat and its metabolites are excreted principally in urine. The ACE inhibitors do not appear to undergo interactions via cytochrome P450 isoenzymes.

Amlodipine: Although dihydropyridines such as nifedipine are highly porphyrinogenic in chick embryo liver cell cultures, amlodipine because of its basic amino side chain (pKa= 8.6) is water-soluble and less likely to be an inducer of ALA-synthase(Gorchein, 1997).

Amlodipine: C.Andersson 2004; 10 patient reports in carriers of AIP. S.Thunell 2004; 4 patient reports in carriers of AIP.

Amlodipine: Report of attack: Kepple, 1997. Reports of uneventful use: 1.Gorchein 1997. 2. Cinemre, 2007.

Amlodipine: Uneventful use reported in 63 patients with acute porphyria. Perindopril: Uneventful use reported in 23 patients with acute porphyria.