Critical factors for pharmacokinetics of zopiclone in the elderly and in patients with liver and renal insufficiency.
Zopiclone, a new hypnotic cyclopyrrolone, undergoes extensive hepatic metabolism. The carrier of hypnotic activity is the parent compound; however, knowledge of its metabolic profile is essential for the understanding of pharmacokinetic changes in various pathophysiological conditions. In 45 healthy young volunteers, zopiclone had a Tmax of 0.5. A first-pass effect of 20% resulted in an absolute bioavailability, F, of 77%. The volume of distribution ratio Vdc/Vdt was 3.2. The plasma half-life (t1/2) was 5.1 h. A metabolic ratio of 3.7 and 4.6 was found for the two main urinary metabolites, N-oxide and N-desmethyl derivatives. No modifications of kinetics were seen after chronic treatment. In eight patients with liver insufficiency, the main changes (delayed Tmax, 3.5 h, higher plasma concentrations with an increased F of 97%, prolonged t1/2 of 8.4 h) were essentially due to a reduced hepatic metabolic clearance, as shown by a decreased metabolic ratio for the two main metabolites. In 18 patients with renal insufficiency, the only major modification was an increased bioavailability (F of 115%) probably due to a relative decrease of the Vdc. In 19 elderly subjects, the main findings were a decreased metabolic clearance, as shown by decreased metabolic ratios, and an inversion of the Vdc/Vdt ratio, evoking the changes seen in renal insufficiency. The increase in F (168%) and the age-dependent increase in plasma t1/2 (8.1 h) in the oldest subjects (over 74 years of age) can be explained by this double mechanism. On the basis of these findings, a reduction of the initial zopiclone dose from 7.5 to 3.5 mg/day is recommended for patients with severe liver insufficiency and patients over 70 years of age with liver insufficiency.
Institut de Biopharmacie Rhône-Poulenc Santé, Antony, France.
J
J
Gaillot
Y
Y
Le Roux
G W
GW
Houghton
J F
JF
Dreyfus
D000328:Adult; D000367:Age Factors; D000368:Aged; D000818:Animals; D053961:Azabicyclo Compounds; D001682:Biological Availability; D004285:Dogs; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D007674:Kidney Diseases / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D010879:Piperazines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D011817:Rabbits; D051381:Rats
D053961:Azabicyclo Compounds; D006993:Hypnotics and Sedatives; D010879:Piperazines; C515050:zopiclone