Pharmacokinetic parameters of β - hydroxyacid simvastatin in experimental hypothyroidism

E.N. Yakusheva, N.M. Popova. Ryazan State Medical University, Department of Pharmacology, Russia

Simvastatin is an inactive prodrug which is readily hydrolyzed to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Aim: to determine changes of pharmacokinetic parameters of β-hydroxyacid simvastatin (βHS) in rabbits with experimental hypothyroidism.

Methods. This study was performed at 6 female Chinchilla rabbits (3900±150g b.v.) with hypothyroidism modeled by oral administration of thiamazol at dose 5 mg/kg b.w. within 21 days. Simvastatin (24 mg/kg b.w.) was administered orally in a single dose before thiamazol administration (basal level) and on the 7th, 14th and 21th days after thiamazol cancellation (test level). To control hypothyroidism thyrotropin (TTH) and thyroxine (T4) levels were measured in the serum by radioimmunoassay method on the 7th, 14th and 21th days after thiamazol cancellation. Concentration of βHS in a blood plasma was defined by HPLC method. Blood samples (5 ml) were collected from ear vein at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours after simvastatin administration. To determine the kinetic parameters of βHS - maximal concentration (Сmax), area under concentration-time curve from 0 to infinity (AUC0- ∞) and last time point to infinity (AUC0-t), Тmax – time of Сmax achievement, volume of distribution (Vd) – was used program Kinetica 5.0. The results were expressed as mean±SD. Statistical comparison analysis was performed by T-test for dependent samples (program Statistica 6.0).

Results. On 7th day of hypothyroidism (7th day after thiamazol cancellation) administration of simvastatin in a single dose caused decrease of T4 concentration, Сmax, AUC0- ∞, AUC0-t of βHS as compared with basal level by 64,2% (р<0,001), 24,2% (р<0,001), 21,3% (р<0,01) and 19,1% (р<0,05) respectively. TTH concentration was higher then reference level by 192,3%, Тmax of βНS – by 50,0 % (р<0,001), Vd – by 53,3% (р<0,01).

On 14th day of hypothyroidism (14th day after thiamazol cancellation) T4 level was lower then basal level by 53,3% (р<0,001), Сmax of βНS by 36,5% (р<0,001), AUC0- ∞ - by 20,6% (р<0,01), AUC0-t - by 28,7% (р<0,05). TTH level, Тmax, Vd of βНS increased as compared with reference level by 146,1% (р<0,001), 50,0 % (р<0,001) and 73,4% (р<0,001) respectively.

On 21th day of hypothyroidism (21th day after thiamazol cancellation) T4 level, Сmax of βНS, AUC0-t decreased from basal level by 34,4% (р<0,001), 19,9% (р<0,001) and 19,5% (р<0,01) respectively. TTH concentration was higher then reference level by 115,3% (р<0,001), Тmax of βНS – by 29,0 % (р<0,001), Vd – by 45,2% (р<0,01). AUC0- ∞ of βНS did not differ significantly from AUC0- ∞ of basal test.

Significant positive correlation was found between Т4 concentration and Сmax (r=0,55; p<0,005), Т4 and AUC0- ∞ (r=0,47; p<0,018), Т4 and AUC0-t (r=0,47; p<0,05), TTH level and Тmax (r=0,79; p<0,001). Significant negative correlation was determine between concentration Т4 and Тmax (r=-0,88; p<0,001), Т4 and Vd (r=-0,55; (р<0,01).

Conclusion. Сmax, AUC0- ∞ decrease and Тmax, Vd of β-hydroxyacid simvastatin increase in rabbits with experimental hypothyroidism. Main pharmacokinetic parameters of β-hydroxyacid simvastatin correlate with T4 and TTH serum levels.