Mixed linear and non-linear disposition of lazabemide, a reversible and selective inhibitor of monoamine oxidase B.
1. Single oral doses (100-300 mg) and multiple oral doses (100-350 mg 12 hourly for 7 days) of lazabemide were administered to 35 young and 40 elderly healthy subjects. Plasma concentrations of unchanged drug were determined to study the dose-concentration relationship. 2. The elimination phase time course of lazabemide concentrations indicated concentration-dependent elimination after both single and multiple dosing. Nevertheless, maximum concentrations and areas under concentration-time curves increased almost proportionally with dose and accumulation after chronic dosing was less than a factor of 2; steady-state concentrations were achieved by the third day of dosing. The apparent half-life determining accumulation was approximately 8-9 h. 3. Drug absorption commenced rapidly after a dose; two components to the absorption process were detectable in young subjects possibly due to simultaneous administration of multiple tablets at the higher doses. 4. Observations after single and multiple dosing were described with a compartmental model allowing for parallel saturable (population mean +/- s.d.: maximum elimination rate Vmax/F: 2.8 +/- 1.4 mg h-1; concentration at half-maximum elimination Km: 36 +/- 19 micrograms l-1) and first-order (CL/F 16 +/- 3.8 l h-1) elimination pathways. No important difference between the young and the elderly subjects was noted in absorption or disposition parameters of lazabemide.
Guentert
T W
TW
Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Holford
N H
NH
Pfefen
J P
JP
Dingemanse
J
J
D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010848:Picolinic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012016:Reference Values
D015507:Drugs, Investigational; D008996:Monoamine Oxidase Inhibitors; D010848:Picolinic Acids; C059303:lazabemide