Clinical Pharmacokinetics of Tacrine

Abstract

Tacrine is currently the only treatment approved for use in Alzheimer’s disease. There is, however, considerable debate over its effectiveness due to conflicting clinical trial results. Most investigators agree, nevertheless, that a definite sub-population of patients do benefit from therapy with tacrine. Tacrine is associated with large pharmacokinetic interindividual variation within both patient and control groups. This is thought to influence both the efficacy and incidence of symptomatic adverse effects in individual patients. Following oral administration of tacrine the drug is rapidly and well absorbed with peak plasma concentrations (C_max) achieved within 0.5 to 3 hours (after a single dose of 20 to 50mg). Tacrine appears to have a wide tissue distribution, which is reflected by its large volume of distribution. High concentrations of the drug were found in the kidney, liver, adrenal gland and brain tissue in animal models. It has a low bioavailability following oral intake, thought to result from extensive first-pass metabolism. Bioavailability can be increased upon rectal administration. The drug is rapidly and extensively metabolised in humans. In vitro metabolism studies have demonstrated the importance of cytochrome P450 (CYP1A2) in the biotransformation of tacrine to 1-, 2-, 4- and 7-hydroxylated metabolites. In humans, mono- and dihydroxylated tacrine and glucuronide conjugates were identified in the urine, which was the primary route of excretion. The elimination half-life of tacrine was short, 1.5 to 2.5 hours after single oral and intravenous doses and 2.9 to 3.6 hours after multiple oral doses. At low doses (l0mg) of tacrine, the pharmacokinetic profile was nonlinear and the oral bioavailability of the drug was disproportionately low in comparison to higher doses of tacrine (20mg). This may reflect saturable hepatic uptake of the parent compound. Both symptomatic and asymptomatic adverse effects occur frequently with tacrine therapy (32 to 80% of patients). These adverse reactions, ranging from predictable cholinergic effects to nonpredictable elevations in serum transaminase levels, can however be reversed by dosage withdrawal and/or adjustment. It has been postulated that the elevated levels of transaminase associated with tacrine therapy in vivo are dependent upon bioactivation of tacrine, mediated by hepatic CYP1A2, to form a toxic compound. Limited data are available regarding the propensity of tacrine to interact with other drugs. In one study, concomitant administration of theophylline led to an alteration of the pharmacokinetics of theophylline, whereas an elevation of plasma tacrine concentrations results from coadministration of cimetidine. Both of these effects are thought to be due to the interaction of the agents with CYP1A2. Therefore, the potential for tacrine to be subject to interactions with other drugs that are substrates of this enzyme should be recognised.