Hydrochlorothiazide: Hydrochlorothiazide is not metabolized by CYP enzymes and does not induce or inhibit these enzymes. It is therefore regarded as probably not porphyrinogenic. Losartan: Losartan is a substrate to CYP3A4, CYP2C9 and CYP2C10. No data is pointing to CYP induction or mechanism based inhibition, and losartan is therefore not suspected to be porphyrinogenic. This is also supported by 33 clinical observations of uneventful use of losartan.

Hydrochlorothiazide: Sulfonamide congener. Losartan: Losartan is an 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. Losartan: Antihypertensive

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). Losartan: Losartan is a prodrug which is converted into its main active metabolite E3174, a carboxylic acid, by CYP3A4, CYP2C9 (Zaidenstein et al. 2001) and CYP2C10 (Sica et al. 2005). In vitro studies indicate that CYP2C9 is the major contributor while CYP3A4 oxidation is only significant at very high concentrations of losartan (Yasar et al. 2001). E3174 is 40 times more potent than losartan (Up to date 2013). Losartan inhibits CYP1A2 (weak), CYP2C19 (weak), CYP2C8 (moderate), CYP2C9 (moderate) and CYP3A4 (weak) (Up to date 2013). In vitro studies state that losartan have modest affinity to CYP2C9 (Taavitsainen et al. 2000). No data is indicating that losartan is a mechanism based inhibitor. Extensive first pass effect. Half-life elimination: Losartan: 1.5-2 hours; E-3174: 6-9 hours.

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. Losartan: Thunell, patient report (n = 1): tolerated. Anderson, patient report (n = 2): tolerated.

Hydrochlorothiazide: Uneventful use reported in 9 patients with acute porphyria. Losartan: Uneventful use reported in 30 patients with acute porphyria.