Hydrochlorothiazide: Hydrochlorothiazide is not metabolized by CYP enzymes and does not induce or inhibit these enzymes. It is therefore regarded as probably not porphyrinogenic. Irbesartan: Irbesartan is metabolized by CYP 2C9, and weak inhibitory potential of this CYP enzyme is observed in vitro. No clinically significant effects on CYP is expected or observed in clinical studies.

Hydrochlorothiazide: Sulfonamide congener. Irbesartan: 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. Irbesartan: Irbesartan 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). Irbesartan: According to in vitro studies irbesartan is primarily metabolized by CYP 2C9, whilst CYP 3A4 has only negligible effect. It has a half-life of 11-15 hours (SPC). In an in vitro study irbesartan was found to have potential for inhibition of CYP 2C9. Irbesartan was also found to be a modest and most likely clinically insignificant inhibitor of CYP 1A2 and 3A4 (Taavitsainen 2000). In another in vitro study, irbesartan was found to be an inhibitor of CYP2C9, but the authors conclude that such inhibition is unlikely to be clinically relevant due to the low free plasma concentration obtained at therapeutic doses (Kamiyama 2007). According to the Sanofi product monograph irbesartan does not inhibit or induce CYP 3A4 (Product monograph Avapro). In vivo studies has shown that irbesartan does not interact with the pharmacokinetics of simvastatin (CYP 3A4 substrate) and warfarin/ tolbutamide (CYP 2C9 substrates) (Marino 2001, Yang 2016).

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. Irbesartan: Uneventful use reported in 10 patients with acute porphyria.