Hydrochlorothiazide: Hydrochlorothiazide is not metabolized by CYP enzymes and does not induce or inhibit these enzymes. It is therefore regarded as probably not porphyrinogenic. 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. 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. Valsartan: Valsartan is used in the treatment of essential hypertension. It is administered orally.

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). 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).

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

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