Pharmacokinetics and sedative effects in healthy subjects and subjects with impaired liver function after continuous infusion of clomethiazole.
OBJECTIVE
Clomethiazole is virtually completely eliminated by hepatic metabolism. This study was designed to assess the impact of liver impairment on its elimination and sedative effects.


METHODS
Eight patients with mild liver impairment (Child-Pugh grade A), eight patients with moderate/severe liver impairment (Child-Pugh grade B/C) and eight healthy subjects of similar age were given 68 mg/kg clomethiazole edisilate according to a 24-h infusion scheme aimed at producing minimum sedation as it was intended for clinical use in patients with stroke. Concentrations of clomethiazole and its active alpha-carbon hydroxylated metabolite NLA-715 were followed in plasma and urine for 96 h and 24 h, respectively. Sedation was monitored using a scale from 1 to 6.


RESULTS
The fraction excreted unchanged in urine was less than 0.2% for clomethiazole and less than 0.4% for NLA-715. Urine concentrations of clomethiazole were strongly correlated (r(2)=0.60) to plasma concentrations and approximately equal to unbound plasma concentrations. Plasma levels of NLA-715 increased steadily during the infusion, eventually reaching mean levels exceeding those of clomethiazole in all groups. Plasma clearance of clomethiazole in subjects with mildly impaired liver function was not statistically different from that of healthy controls (40 l/h vs 44 l/h). In subjects with moderate/severe liver impairment, there was a 50% reduction in clearance. Sedation was not observed except in two subjects in the Child-Pugh A group showing mild sedation.


CONCLUSIONS
The reduced clomethiazole clearance in patients with moderate/severe liver impairment seems to call for a reduction of clomethiazole dosage. However, sedation was not observed in this group at the investigated dose level.
AstraZeneca R&D Södertälje, 151-85, Södertälje, Sweden. carina.centerholt@astrazeneca.com
Carina
C
Centerholt
Marianne
M
Ekblom
Tomas
T
Odergren
Olof
O
Borgå
Gabriela
G
Popescu
Karl-Heinz
KH
Molz
Andrea
A
Couturier
Angelika
A
Weil
D019540:Area Under Curve; D002110:Caffeine / Q000493:pharmacokinetics; D002719:Chlormethiazole / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007208:Indocyanine Green / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology; D008107:Liver Diseases / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D013844:Thiazoles / Q000097:blood / Q000652:urine; D013997:Time Factors
D006993:Hypnotics and Sedatives; C406476:NLA 715; D018696:Neuroprotective Agents; D013844:Thiazoles; D002719:Chlormethiazole; C034739:clomethiazole edisylate; D002110:Caffeine; D007208:Indocyanine Green