Hydrochlorothiazide: Hydrochlorothiazide is not metabolized by CYP enzymes and does not induce or inhibit these enzymes. It is therefore regarded as probably not porphyrinogenic. 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. Valsartan: Valsartan is eliminated mainly as unchanged drug. A small portion of the drug is metabolized by CYP 2C9, and some weak inhibitory potential is observed in vitro. No clinically significant effects on CYP is expected or observed in clinical studies.

Hydrochlorothiazide: Sulfonamide congener. 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). Valsartan: Angiotensin II receptor antagonist.

Hydrochlorothiazide: Hydrochlorothiazide is a thiazide diuretic that inhibits reabsorption of electrolytes in the distal tubule, leading to increased excretion of water, sodium, chloride, potassium, magnesium and other electrolytes. It is administered orally. 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. Valsartan: Valsartan is used in the treatment of essential hypertension. It is administered orally.

Amlodipine: Possibly significant.

Hydrochlorothiazide: Hydrocholorothiazide is not metabolized, but is eliminated mainly unchanged in the urine. The plasma half-life is about 9,4 – 13 hours (Beermann 1976, Drugbank, SPC). 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). Valsartan: About 80 per cent of administered dose of valsartan is excreted in unchanged form. A small portion of the drug is metabolized by CYP 2C9 to the inactive metabolite 4-OH-valsartan (Nakashima 2005, SPC). It has a half- life of about 5-9 hours (drugbank). Valsartan has been shown not to inhibit human cytochrome P450 enzymes CYP1A, 2A6, 2C19, 2D6, 2E and 3A in vitro in concentrations up to 100µM. A weak and clinically insignificant inhibition of CYP 2C9 was seen (Taavitsainen 2000). In an in vivo study, no drug-drug interaction was observed upon co-administration of Valsartan/sacubitril with digoxin/warfarin in healthy subjects (Ayalasomayajula).

Hydrochlorothiazide: In an in ovo study of chick embryo livers, methyclothiazide, another thiazide drug, was found to have potential for induction of ALAS, whereas hydroclorothiazide and other thiazides was found not to have these effects (Anderson 1981). The results from these types of animal studies are not directly transferable to human, and cannot be given weight in the judgement of porphyrinogeniciry of drugs (Hift 2011). 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).

Hydrochlorothiazide: Thunell, patient report (n=1): tolerated. Andersson, patient reports (n=10): tolerated. Peters: On basis of clinical experience probably not porphyrinogenic. 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.

Hydrochlorothiazide: Uneventful use reported in 9 patients with acute porphyria. Amlodipine: Uneventful use reported in 63 patients with acute porphyria. Valsartan: Uneventful use reported in 15 patients with acute porphyria.