The Relation between the Dose of and the Induction of Drug Interaction by Cimetidine. A Survey of the Literature and the Alteration of Pharmacokinetics of Theophylline.

Cimetidine (CIM), a histamine H2-receptor antagonist, has been demonstrated to reduce the clearance (CL) of a number of drugs. Up to date, 29 drugs, whose CLs are reduced by the coadministration of CIM, are listed under their package insert. We reviewed the original articles investigating the potential drug interaction between CIM and these drugs, and analyzed the relationship between the daily dosage of CIM and the alteration of the CL of the coadministered drugs.The decrease in the CL in the coadministration of CIM varied greatly from chlordiazepoxide with the largest decrease (56.7%) to mexiletine with the smallest (6.0%). The dose of the CIM described in original articles also varied greatly with the largest dose 2, 400 mg/day and the lowest 300 mg/day. A dose of over 800 mg/day of CIM, which is the upper limit of the usual dose in Japan, comprised 98% of all reported cases. A 1, 200 mg/day dose (16.6 mg/kg/day) of CIM, which was the most frequent dose described in the literature, was 2.5 times higher than the 400 mg/day dose (6.7 mg/kg/day) which is the usual dose in recent years in our country.The CL and serum trough concentration of theophylline (TP) were measured before and after the oral coadministration with a dosage of 400 mg/day or 800 mg/day of CIM for 5 days in four healthy subjects. The alteration in the serum trough concentration (about a 35% increase) and the CL (about 20% decrease) of TP induced by the coadministration of 800 mg/day of CIM, was much greater than that observed after the coadministration at 400 mg/day.These results suggest that the uniform change in prescriptions only based on the names of the drugs used in combination must be reexamined, and that it is necessary to improve the drug interaction-check system based on scientific evidence. after carefully evaluating the dose of the drug used.