CLINICAL PHARMACOKINETICS OF DRUGS FOR ALZHEIMERS-DISEASE

Pharmacological treatment of patients with Alzheimer's disease is beco ming more important, as evidenced by the number of drugs being develop ed in different countries. It has been shown in the majority of clinic al trials that cholinesterase inhibitors, such as tacrine (tetrahydroa minoacridine), are able to induce beneficial effects in cognition and memory. Tacrine, Like most of the other oral antidementia agents, is r apidly absorbed from the gastrointestinal tract. It is excreted mainly through the kidney, with a terminal elimination half-life of about 3 hours. Tacrine has nonlinear pharmacokinetics and there are large inte rindividual differences in pharmacokinetic parameters after oral, intr avenous and rectal administration. A positive relationship between cog nitive changes and plasma tacrine concentrations has been recently des cribed. Similarly, velnacrine exhibits evidence of nonlinearity in som e pharmacokinetic parameters, but renal excretion is a minor route of elimination for this drug. Pharmacokinetic data pertaining to eptastig mine, a third cholinesterase. inhibitor, is more limited. However, the drug is rapidly distributed to the tissues after oral administration and readily enters the central nervous system, where it can be expecte d to effectively inhibit acetylcholinesterase in the brain for a prolo nged period. Pharmacokinetic data for the nootropic agents are more li mited. However, of the 3 agents reviewed only pramiracetam penetrates the central nervous system (CNS) poorly. Indeed, oxiracetam crosses th e blood-brain barrier and persists for longer in the CNS than in the s erum. Selegiline (deprenyl), a neuroprotective agent, is readily absor bed from gastrointestinal tract. It is metabolised mainly in the liver , and to a minimal extent in the lung or kidneys. The steady-state con centrations of metabolites inthe cerebrospinal fluid (CSF) and serum a re very similar, reflecting their easy penetration into the CNS. Idebe none, another neuroprotective agent, likewise is rapidly absorbed and achieves peak concentrations in the brain comparable to those in plasm a. Similarly, CSF concentrations of metabolites of ST 200 (acetyl-L-ca rnitine) parallel those in plasma, suggesting that they easily cross t he blood-brain-barrier. Gangliosides (GM1) can be given intramuscularl y or subcutaneously, but the latter route of administration provides a concentration 50% higher both in the serum and the ganglioside fracti on. However, because of its longer elimination, the intramuscular rout e is the best form of administration when the brain is the target orga n for the treatment. Absorption of nimodipine is quite rapid. The phar macokinetics of nimodipine during multiple-dose treatment have not bee n studied extensively; however, the drug does not appear to accumulate during repeated administration of standard doses. Nimodipine has line ar pharmacokinetics and is subject to interindividual variability. It is primarily excreted in the urine, but 32% of the dose is excreted in the faeces, possibly as a consequence of biliary excretion. To achiev e adequate drug concentrations in the brain, different methods have be en devised, both invasive (implantable drug infusion pumps and polymer drug-delivery systems, neural transplantation, etc.) and noninvasive (prodrugs microencapsulated within biocompatible polymers that can pro tect the drug from degradation, etc.) methods. These methods may provi de more effective drug delivery into the CNS, and pharmacokinetic data should be determined when these methods of drug delivery are being as sessed in clinical trials.