Pharmacokinetics and bioavailability of cimetidine in humans.

Cimetidine given orally without food after an overnight fast produces a blood concentration curve with a pronounced second peak that does not appear after parenteral administration or when the drug is taken with food. The following interpretation of this kinetic phenomenon is proposed: 1. The drug cumulates in a tissue or organ that is well perfused in the first-pass transfer. 2. The hepatic parenchymal tissue and the bile phase are the most likely storage areas. 3. The high capacity of the cumulation may be due to the formation of conjugates or other modifications of the drug with a pronounced affinity for the hepatic-biliary system. 4. The rate of cumulation is much higher in the first-pass transfer than from the systemic circulation, possibly due to the difference in the drug concentrations and the conjugation rate. 5. The cumulation appears to occur by a competitive process. 6. Absorbed elements of food seem to compete in this process. 7. The second peak apparently is the result of a rapid release of drug and bioreversible drug compounds from the hepatic-biliary system with subsequent reabsorption. 8. This release may occur spontaneously but appears to be triggered by food intake. A pharmacokinetic model constructed according to this interpretation showed good agreement with data from oral, intravenous, and intramuscular administration. The special problems associated with the evaluation of bioavailability in the presence of reabsorption are discussed.