Pharmacokinetics and pharmacodynamics of oxazepam and metabolism of paracetamol in severe hypothyroidism.

Abstract

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-' kg-' (0.40-1.25) to 1.22 ml min-' kg-' (0.66-1.94) and from 9.3 ml min-' kg-" (5.2-14.2) to 15.9 ml min-' kg-l (7.8-21.8), respectively (P < 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 < 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-' kg-' (1.64-4.40) and 4.70 ml min-' kg-' (3.18-5.70) following replacement therapy (P < 0.01). This increase was associated with a comparable increase in the partial clearance to the glucuronide metabolite: 1.86 ml min-' kg-' to 2.70 ml min-' kg-'.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.

Population pharmacokinetics of single-dose intravenous paracetamol in children

“…propacetamol, increased to 84% of the value of older children by the end of the first year of life. The value of CL obtained (16.5 litre h 21 ) in our study is higher than the 13.2 litre h 21 reported by Wurthwein and colleagues, 5 but similar to that reported by Anderson and colleagues 15 of 16 litre h 21 .…”

“…The population parameter Because the additive term of the residual error variance approached 0, it was removed resulting in a proportional error model. The residual (unexplained) variability in the final model was reduced to 17.7% (from 26.6% in the base model) corresponding to an SD of 2.51 mg litre 21 at the mean detected paracetamol concentration of 14.7 mg litre 21 .…”

“…The wavelength of detection was fixed at 244 nm on a Waters 486 Absorbance Detector (Waters Ltd, Elstree, UK) to quantify the analytes. The lower limit of quantification (LLOQ) for the method was 900 pg on column, equivalent to 1 mg litre 21 of whole blood. The intra-and inter-day coefficient of variation (CV%) at the LLOQ (1 mg litre 21 ) ranged from 14.3% to 20%.…”

“…The intra-and inter-day coefficient of variation (CV%) at the LLOQ (1 mg litre 21 ) ranged from 14.3% to 20%. The validation range for the assay was 1-100 mg litre 21 . The mean relative error (RE%) was always ,15% at 3 and 30 mg litre 21 (11% and 7%, respectively).…”

Glucuronidation of Drugs

“…Limited data are available for glucuronidation. A more extensive study with this model drug (n = 8) and oxazepam (n = 10) was performed by Sonne et al (1990b) in patients with severe hypothyroidism before and after treatment with levothyroxine. A more extensive study with this model drug (n = 8) and oxazepam (n = 10) was performed by Sonne et al (1990b) in patients with severe hypothyroidism before and after treatment with levothyroxine.…”