title: Clinical pharmacokinetics of intravenous and oral 9-amino-1,2,3,4-tetrahydroacridine, tacrine.
abstract: The pharmacokinetics of 9-amino-1,2,3,4-tetrahydroacridine; tacrine, THA, was studied after intravenous administration and following the first and last oral doses of a seven week clinical trial involving 8 patients with amyotrophic lateral sclerosis, ALS. Two surgical patients given intravenous THA for reversal of postoperative sedation were also included. Plasma concentration of THA and in some cases the metabolite, 1-hydroxy-THA, were assayed using a selective and sensitive method with high performance liquid chromatography. After an intravenous dose of 30 mg THA, the plasma concentrations were fitted to a two-compartment model. Plasma clearance showed a threefold interindividual variation with a mean of 2.42 l.h-1. Volume of distribution, V alpha varied 100-680 l with a mean of 349 l. The plasma half-lives of distribution and elimination were 1.8 and 98.2 min, respectively. Oral bioavailability showed large interindividual differences and ranged 6-36% in the four subjects studied. After seven weeks treatment with oral THA, plasma concentrations immediately prior to medication were below 10 ng/ml in three patients and above 100 ng/ml in two patients. At the same occasion the plasma metabolite concentrations considerably exceeded those of THA. THA medication was associated with side effects in the majority of the patients.
authors.affiliation: Hospital Pharmacy, University Hospital, Uppsala, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Hartvig
authors.forename: H
authors.initials: H
authors.lastname: Askmark
authors.forename: S M
authors.initials: SM
authors.lastname: Aquilonius
authors.forename: L
authors.initials: L
authors.lastname: Wiklund
authors.forename: B
authors.initials: B
authors.lastname: Lindström
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000609:Aminoacridines / Q000493:pharmacokinetics*; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000378:metabolism; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004244:Dizziness / Q000139:chemically induced; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D013619:Tacrine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000609:Aminoacridines; D013619:Tacrine