Changes In Cmax Research Articles

Pharmacokinetics of gamma-hydroxybutyric acid in alcohol dependent patients after single and repeated oral doses.

1. The pharmacokinetics of gamma-hydroxybutyric acid (GHB) were studied in 10 alcohol dependent subjects after single and repeated therapeutic oral doses (25 mg kg-1 every 12 h for 7 days). 2. GHB was readily absorbed and rapidly eliminated (tmax = 20-45 min; mean t1/2z 27 +/- 5 s.d. min). Urinary recovery of unchanged GHB was negligible (less than 1% of the dose). gamma-butyrolactone was not detected in either plasma or urine, indicating that lactonization of GHB does not occur in vivo. 3. The multiple-dose regimen resulted neither in accumulation of GHB nor in time-dependent modification of its pharmacokinetics. 4. In five subjects, the data were consistent with nonlinear elimination kinetics of GHB. Administration of a 50 mg kg-1 dose to these subjects resulted in significant increases in dose-normalized AUC, t1/2z and mean residence time. 5. Doubling of the dose also resulted in a significant increase in tmax with little change in Cmax. 6. At the administered doses, GHB did not accumulate in the plasma and caused no serious side effects.

Evaluation of hepatic dysfunction in endotoxin pretreated rats using tolbutamide as a marker

The pharmacokinetics of tolbutamide (TB) have been studied in endotoxin pretreated rats with the aim of evaluating TB as a marker for endotoxin effects. Endotoxin dose of 10 mg/kg resulted in a 50% rate of mortality. TB was i.v. administered 24 h. after endotoxin dosing. Clearance (Cl) decreased by approximately 2/3 of its value, area under the curve (AUC) and half-life (t1/2) in the pretreated animals were an average 1.5 times the values for the respective controls. Volume of distribution (Vd) increased by 10% approximately. These findings suggest that endotoxin pretreatment may cause hepatic damage by producing a decrease in Cl and an increase in the t1/2 of TB. But, SGOT levels in pretreated animals were not significantly different. This phenomenon may be explained by the increase in plasma protein binding of TB during endotoxin pretreatment, which decreases the free fraction of the drug in plasma available for metabolism. Endotoxin increased tmax of hydroxy-TB, while no change in Cmax was observed. Since tmax is inversely related to the formation and elimination rates of hydroxy-TB, an increase in tmax may be due to the decrease in both elimination rates. No change in Cmax may be due to the decrease in the rate of formation which is equivalent to the decrease in the rate of elimination of hydroxy-TB.

Different alterations of nuclear triiodothyronine receptor capacity in liver and kidney induced by starvation and triiodothyronine administration.

Many studies have shown alterations in the number of nuclear triiodothyronine receptor (NT3R) under pathophysiologic situations. Most of these studies were performed on the rat liver and it is not known whether NT3R in different tissues exhibits an alteration similar to that in the liver. We compared the change of nuclear receptor capacity for T3 in the liver and kidney during starvation and after T3 injection. Fasting for 72 h decreased maximal binding capacity (Cmax) in the rat liver receptor to 67% of the control, while it did not significantly change Cmax in the kidney. These changes in Cmax were parallel to those of nuclear protein concentrations in both tissues. Daily sc injection of T3 (20 micrograms/100 g body weight) for 3 days also caused the different alteration of Cmax in the liver and kidney. After T3, hepatic NT3R increased to 182% of the control, but renal NT3R increased only to 136%. Association constants were the same in all groups. These results show that changes of NT3R capacity under some conditions vary in different tissues.