Are there any pharmacokinetic interactions between sulfasalazine and metformin or atenolol? Could a

Fråga: Are there any pharmacokinetic interactions between sulfasalazine and metformin or atenolol? Could any of the latter drugs be co-responsible for elevated liver enzymes during sulfasalazine therapy? The question concerns a 49-year-old woman with psoriatic arthritis, hypertension and type 2 diabetes. For several years she had been on therapy with sulfasalazine 3 g/day for her arthritis. Her other medications included ibuprofen up to 1600 mg/day, glibenclamide unknown dose, furosemide 30 mg/d, omeprazole 20 mg/d, paracetamol 0.5-1 g/d, levothyroxine unknown dose, cilazapril 5 mg/d and hydrochlorothiazide 12.5 mg/d. Liver enzyme levels were continuously monitored because of the sulfasalazine therapy. In the spring of 2002 a first slight elevation of liver enzymes were noted, which did not prompt a change of therapy. In the fall of 2002 metformin medication was initiated and titrated up to 850 mg x 3. In March 2003, 25 mg of atenolol were added to the medications of the patient. In April the ibuprofen medication was discontinued. At the end of May 2003 ALT peaked at 1.44 (<0.60). This prompted the discontinuation of sulfasalazine. Approximately a week later ALT had decreased to 1.03.

Sammanfattning: No reports of interactions between sulfasalazine and atenolol or metformin have been found. Neither the metabolic pathways nor the reported side effects of atenolol or metformin specifically support the notion that either of these drugs contributed to elevated liver enzymes in this case. The most probable cause of this finding thus seems to be the sulfasalazine therapy in itself.

Svar: Sulfasalazine is broken down in the GI-canal to sulfapyridine, which is absorbed, and 5-aminosalicylate, which is poorly absorbed and mainly retained in the feces. Sulfapyridine is acetylated in the liver and renally excreted as acetylsulfapyridine. The degree of acetylation is genetically determined. Slow acetylators (60% of the Caucasian population) might be more prone to sulfa-related adverse effects. Elevated liver enzymes is a common side effect of sulfasalazine (1). Sulfasalazine-induced hepatitis appears not to be dose-related, and has been described in fast acetylators (6).

Metformin is completely renally excreted in an unchanged form. No metabolites have been found in man (1). Hepatic side effects of metformin are extremely rare. Only three cases have been reported in the literature (2).

Atenolol is almost entirely excreted renally in its native form (1,5). Reports of hepatotoxicity are rare (3).

Standard textbooks do not quote any known drug interactions between sulfasalazine and metformin or atenolol (4,5). A Medline search could not identify any published case reports of the sort.