Oral Pharmacokinetic Drug-drug Interactions between Amifampridine and Acetaminophen in Rats

Abstract

Amifampridine, the first-line medication for Lambert-Eaton myasthenic syndrome (LEMS), is extensively metabolized by N-acetyltransferase 2 (NAT2). Drug-drug interactions (DDIs) can occur when co-administered with a NAT2 inhibitor and amifampridine. Acetaminophen is a widely used analgesic for mild to moderate pain, which is also known as a NAT2 inhibitor. In this work, we studied the effects of acetaminophen on the amifampridine pharmacokinetics in rats. Both acetaminophen (300 mg/kg) and amifampridine (2 mg/kg) were administered orally. In acetaminophen-treated rats, the systemic exposure to amifampridine significantly increased, and the ratio of the area under the plasma concentration-time curve for 3-N-acetylamifampridine to amifampridine (AUCm/AUCp) decreased markedly, which is likely due to the inhibition of NAT2 by acetaminophen. Also, the urinary amount excreted was increased in the acetaminophen-treated group, but the renal clearance remained unchanged. This oral pharmacokinetic drug-drug interaction study showed that orally administered acetaminophen significantly inhibits the NAT2-based metabolism of amifampridine and may cause meaningful DDIs.