Pharmacokinetics and pharmacodynamics of oxazepam and metabolism of paracetamol in severe hypothyroidism.
1. The effect of severe hypothyroidism on the pharmacokinetics and pharmacodynamics of oxazepam 15 mg given orally (n = 10) and the metabolism of paracetamol 750 mg given intravenously (n = 8) was investigated before and after treatment with levothyroxine. 2. The median total and unbound clearance of oxazepam increased significantly during the study period from 0.78 ml min-1 kg-1 (0.40-1.25) to 1.22 ml min-1 kg-1 (0.66-1.94) and from 9.3 ml min-1 kg-1 (5.2-14.2) to 15.9 ml min-1 kg-1 (7.8-21.8), respectively (P less than 0.01). 3. The elimination half-life of oxazepam was prolonged by hypothyroidism to a median (range) value of 9.3 h (5.4-21.9) compared with 7.5 h (4.8-10.5) in the euthyroid state (P less than 0.05). 4. Hypothyroidism did not affect the protein binding of oxazepam; median values of the free percentage being 8.2% as compared with 7.7% when euthyroid. 5. The median (range) clearance of paracetamol under hypothyroid conditions was 3.12 ml min-1 kg-1 (1.64-4.40) and 4.70 ml min-1 kg-1 (3.18-5.70) following replacement therapy (P less than 0.01). This increase was associated with a comparable increase in the partial clearance to the glucuronide metabolite: 1.86 ml min-1 kg-1 to 2.70 ml min-1 kg-1. 6. Hypothyroidism was associated with decreased performance in a finger tapping test that was exacerbated by oxazepam. When the patients were euthyroid oxazepam did not produce any effect.
Sonne
J
J
Department of Internal Medicine F, Gentofte Hospital, Denmark.
Boesgaard
S
S
Poulsen
H E
HE
Loft
S
S
Hansen
J M
JM
Døssing
M
M
Andreasen
F
F
D000082:Acetaminophen / Q000008:administration & dosage / Q000378:metabolism*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007037:Hypothyroidism / Q000378:metabolism*; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010076:Oxazepam / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
D000082:Acetaminophen; D010076:Oxazepam