Premium
Mechanism of alterations in propylthiouracii disposition after long‐term therapy
Author(s) -
Giles H G,
Long J P,
Orrego H,
Sellers E M
Publication year - 1982
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1982.78
Subject(s) - medicine , endocrinology , thyroid , volume of distribution , hormone , pharmacokinetics , chemistry
Alterations in propylthiouracii (PTU) disposition after long‐term use in patients treated for alcoholic liver disease (ALD) have not been reported. We gave PTU (3.3 mg / kg / day intraperitoneally) for 24 days to naive male Sprague‐Dawley rats (n = 10). Clearance of PTU in these animals (1.11 ± 0.04 ml / min / kg, x̄ ± SEM) was slightly less than in controls (1.28 ± 0.05 ml/min/kg, n = 8, P = 0.02) as a consequence of drug‐induced hypothyroidism (thyroid weight in PTU‐treated rats = 78.0 ± 7.2; controls = 29.6 ± 2.1 mg/kg, P < 0.01). PTU clearance in thyroidectomized rats (0.74 ± 0.04 ml/min/kg, n = 12; thyroid‐stimulating hormone [TSH] = 3.3 ± 0.2; μIU/ml) was less (P < 0.01) than in sham‐operated controls (1.47 ± 0.12 ml/min/kg; n = 9; TSH = 1.9 ± 0.2 μIU/ml). Neither plasma free fraction (25.0 ± 0.8%) nor apparent volume of distribution (0.72 ± 0.02 l/kg) in thyroidectomized rats differed from control values (26.4 ± 1.4%, 0.73 ± 0.02 l/kg). In ALD patients (four men; two women) tested with PTU (300 mg IV) before and after PTU therapy (150 mg b.i.d. orally) for 28 days, TSH rose from 3.6 ± 1.0 to 7.0 ± 2.6 μIU/ml (P = 0.03), but free PTU clearances rose in all patients (range 2.2% to 48.4%, P = 0.03). Free clearance before treatment was 1047 ± 131 and after treatment it was 1223 ± 139 ml/min; in 14 healthy subjects it was 1454 ± 86 ml/min. The alteration in clearance correlated positively (r = 0.91, P < 0.02) with the severity of disease as assessed by a composite clinical and laboratory index; in the more severely diseased patients there was the most alteration in both clearance and severity of ALD. There are two opposing events that determine net PTU disposition; biochemical hypothyroidism reduces PTU clearance, but improvement in hepatic function overcomes such an effect. The net increase in PTU free clearance reduces efficacy during long‐term dosing. Clinical Pharmacology and Therapeutics (1982) 31, 559–563; doi: 10.1038/clpt.1982.78