OBJECTIVETo study the pharmacokinetics of propranolol and metoprolol in rats after acute exposure to high altitude.

METHODSWistar rats were randomly assigned into 4 groups for treatment with intragastric administration of propranolol or metoprolol after acute exposure to high altitude (4010 m) or normal altitude (50 m). Venous blood samples were collected from the rats at different time points after drug administration to determine the drug concentrations in the plasma and plasma ultrafiltrate using liquid chromatography-mass spectrometry (LC-MS/MS).

RESULTSThe protein binding rate of propranolol was significantly increased but that of metoprolol remained unchanged after acute exposure to high altitude. Compared with the rats exposed to normal altitude, the rats with acute exposure to high altitude showed significant alterations in the pharmacokinetic parameters of the drugs, shown by increased Cmax and AUC, prolonged t1/2 and MRT, and lowered Clz/F of propranolol, and by increased Tmax and prolonged t1/2 and MRT of metoprolol without obvious changes of the parameters of the compartmental model.

CONCLUSIONSignificant changes in the pharmacokinetics of propranolol and metoprolol occur in rats after acute exposure to high altitude possibly in relation to, apart from the changes in plasma protein binding ratio and blood gas, alterations in metabolic enzyme activities, increased blood viscosity, and species and general conditions of the animals.

Altitude ; Animals ; Chromatography, Liquid ; Metoprolol ; pharmacokinetics ; Propranolol ; pharmacokinetics ; Protein Binding ; Rats ; Rats, Wistar ; Tandem Mass Spectrometry

OBJECTIVETo study the correlation between the absorption rate constants of beta-adrenoreceptor antagonists in rat small intestinal segments and their molecular structural parameters.

METHODSThe net atomic charges and the molecular volumes of 11 beta-adrenoreceptor antagonists were obtained with the semiempirical self-consistent field molecular orbital calculation CNDO/2 method and Mont Carlo method respectively, using the minimum energy conformation obtained from the optimization of the standard molecular geometry with the molecular mechanics MM+ method. The stepwise multiple regression analysis was used to obtain the correlation equations.

RESULTSThe absorption rate constants of beta-adrenoreceptor antagonists in rat jejunum or ileum were well linearly correlated with the sum of the net charges of all hydrogen atoms and the molecular volumes. The beta-adrenoreceptor antagonist with higher lipophilicity, weaker hydrogen-bonding potential,and smaller molecular volume had greater absorption rate constants.

CONCLUSIONThe absorption rate constants of beta-adrenoreceptor antagonists in rat small intestinal segments are mainly related with their lipophilicity,hydrogen-bonding potential and molecular size.

Adrenergic beta-Antagonists ; chemistry ; pharmacokinetics ; Animals ; Intestinal Absorption ; Intestine, Small ; metabolism ; Metoprolol ; pharmacokinetics ; Molecular Structure ; Nadolol ; pharmacokinetics ; Propranolol ; pharmacokinetics ; Rats ; Regression Analysis

BACKGROUND/AIMS: This study was designed to determine the effect of hepatic fibrotic severity on pharmacokinetics of propranolol in CCl4-treated rats. METHODS: 1 mL/kg of 10% CCl4 in olive oil was injected intramuscularly to rats twice weekly for 4, 6, 8 and 10 weeks, respectively (n=6). Control (n=6) was a sham-injected equal dose of olive oil for 10 weeks. After intravenous bolus injection of 2 mg/kg propranolol to rats, the serum propranolol concentrations were analyzed for 4 hours at various time points by a HPLC-fluorimetric system, and pharmacokinetic parameters such as C0, MRT, AUC, Vdss, t1/2( ) and CLp were determined. Then, a small amount of hepatic tissue was obtained and subjected to determination of the hepatic 4-hydroxyproline content, which confirmed the hepatic fibrotic severity. RESULTS: The serum concentrations of propranolol at 0.5, 1, 2 and 4 hours were significantly increased in CCl4-treated rats (p<0.01). In proportion to the duration of CCl4 treatment, C0 and AUC were significantly increased, and Vdss and CLp were significantly decreased (p<0.001). But MRT and t1/2( ) were not significantly changed. The hepatic 4-hydroxyproline content was gradually increased in CCl4-treated rats (p<0.001). CONCLUSION: Gradual changes in pharmacokinetic parameters of propranolol were seen to be dependent on the hepatic fibrotic severity. We suggest that gradual dosage modification, according to their hepatic fibrotic severity, is necessary for many drugs administered to patients with chronic liver disease.
Animals ; Area Under Curve ; Humans ; Hydroxyproline ; Liver Diseases ; Olea ; Pharmacokinetics ; Propranolol* ; Rats* ; Olive Oil

BACKGROUND: This study was designed to determine the relationship of propranolol pharmacokinetic parameters with portosystemic shunt in CCl4-induced cirrhotic rats. METHODS: Cirrhotic rats(n=6) were induced by intramuscular injection of CCl4 in olive oil(two time per weeks) for 12 weeks. Controls (n=6) were injected intramuscularly with the same dose of olive oil for 12 weeks. We evaluated the amount of portosystemic shunt by thallium-201 per rectal scintigraphy. After intravenous bolus injection of propranolol (2mg/kg) to rats, the serum propranolol concentrations were analyzed by a HPLC-fluorimetric detector system. Pharmacokinetic parameters such as C0, AUC, t(1/2(beta)), and CLp were determined in each group. Then, a small amount of heptic tissue was obtained and subjected to determination of the hepatic collagen content by quantitating 4-hydroxyproline and were inspected by microscope after hematoxylin and eosin stain. RESULTS: In liver biopsy, liver fibrosis progressed in CCl4-induced cirrhotic rats. The serum concentrations of propranolol were significantly (p < 0.01) elevated in CCl4-induced cirrhotic rats. Mean amount of 4-hydroxyproline, mean H/L ratio, and mean AUC in CCl4-induced cirrhotic rats was significantly (p < 0.01) higher than that in control rats. There was a relationship between AUC, H/L ratio, and amount of 4-hydroxyproline. CONCLUSION: H/L ratio may help in the selection of drug dosage (especially blood flow dependent drug) in pre-clinical studies for chronic liver disease during the drug development process.
Animals ; Carbon Tetrachloride Poisoning/*complications ; Chromatography, High Pressure Liquid ; English Abstract ; Liver Cirrhosis, Experimental/*metabolism/physiopathology ; Portal System/physiopathology ; Propranolol/*pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Thallium Radioisotopes/diagnostic use