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

The hydroxypropyl methylcellulose (HPMC) matrix tablet containing metoprolol succinate (MS) as a model drug was obtained by wet method compression tablet. The effects of the amount and viscosity of HPMC, the preparation method, compressing pressure, the amount of ethycellulose (EC), the pH of dissolution medium and the speed of basket rotation on the drug release from the matrix tablets were evaluated. The results showed that the release rate of metoprolol succinate from HPMC matrix tablets followed Higuchi equation. The release mechanism was in line with the synthetical effect of diffusion and corrosion. Drug release was influenced by the amount and viscosity of HPMC, the amount of EC in matrices, the preparation method and compressing pressure, etc. Drug release was not influenced by the pH of dissolution medium used, and not by the speed of basket rotation, either.
Delayed-Action Preparations ; Drug Compounding ; Hypromellose Derivatives ; Methylcellulose ; analogs & derivatives ; chemistry ; Metoprolol ; administration & dosage ; analogs & derivatives ; pharmacokinetics ; Pharmaceutic Aids ; chemistry ; Pharmaceutical Preparations ; chemistry ; Tablets ; Viscosity

To prepare transdermal drug delivery system (TDDS) of felodipine and metoprolol and to study its pharmaceutical characteristics, pharmacokinetics and bioavailability in rabbits, an HPLC assay was established for the simultaneous determination of felodipine and metoprolol in the permeation receptor and patch. The permeation rate and permeation mechanism of felodipine-metoprolol-TDDS through rabbit skin in vitro was examined. The determination of drug content, the examination of content uniformity and stability of the TDDS were carried out. GC-ECD assays were established for the determination of felodipine and metoprolol in plasma separately and then employed to study the pharmacokinetics and bioavailability of felodipine and metoprolol after a single dose of oral or transdermal administration in rabbits. The results indicated that the permeation of flodipine and metoprolol from the patch through excised rabbit skin exhibited zero-order kinetic characteristics. The determination of drug content and the quality control of content uniformity of the patch accorded with Pharmacopoeia of the People's Republic of China of 2005 edition and the pharmaceutical characterization showed good stability. In contrast to oral delivery, relatively constant, sustained blood concentration with minimal fluctuation and prolonged peak time were observed over a long period after transdermal administration. The relative bioavailability of felodipine and metoprolol were 275.37% and 189.76% versus oral administration respectively. It was evident that the felodipine-metoprolol-TDDS exhibited good controlled release properties that satisfied the demands of original design that enhancing bioavailability and maintaining appropriate blood levels for a prolonged time without adverse effects associated with frequent oral administration.
Administration, Cutaneous ; Animals ; Antihypertensive Agents ; administration & dosage ; blood ; pharmacokinetics ; Area Under Curve ; Azepines ; chemistry ; Biological Availability ; Cyclohexanols ; chemistry ; Delayed-Action Preparations ; Drug Delivery Systems ; Drug Stability ; Felodipine ; administration & dosage ; blood ; pharmacokinetics ; Female ; Male ; Metoprolol ; administration & dosage ; blood ; pharmacokinetics ; Monoterpenes ; chemistry ; Propylene Glycols ; chemistry ; Rabbits ; Skin Absorption

CYP1A2, CYP2D6 and N-acetyltransferase activities were estimated in 100 patients with bladder cancer and 84 control subjects from measurements of theophylline, metoprolol and isoniazid and their metabolites in urine, respectively. The frequency of occurrence of slow acetylators of isoniazid and poor metabolizers of metoprolol were 16.7% and 1.2% in the control group and 16.3% and 2.0% in the cancer patient group. These differences were not significant. The recovery ratio of 1-methyluric acid(1-MU) from theophylline was significantly higher in patients with bladder cancer than in control subjects(0.340 +/- 0.016 versus 0.260 +/- 0.020, p< 0.05). The 1-MU recovery ratio was a significant, independent risk factor among the metabolic capacities tested as shown by logistic regression analysis, controlling for N-acetylation of isoniazid, hydroxylation of metoprolol, age, sex, and smoking. We concluded that the capacity for 3-demethylation of theophylline, as a reflection of CYP1A2 activity, is significantly associated with increased risk of nonoccupational urinary bladder cancer.
Acetylation ; Adult ; Aged ; Amines/metabolism ; Bladder Neoplasms/enzymology/*epidemiology ; Carcinoma, Transitional Cell/enzymology/*epidemiology ; Case-Control Studies ; Cytochrome P-450 CYP1A2 ; Cytochrome P-450 CYP2D6 ; Cytochrome P-450 Enzyme System/metabolism/*urine ; Disease Susceptibility ; Enzyme Induction ; Female ; Human ; Isoniazid/*pharmacokinetics ; Korea/epidemiology ; Logistic Models ; Male ; Methylation ; Metoprolol/*pharmacokinetics ; Middle Age ; Mixed Function Oxygenases/metabolism ; Mixed Function Oxygenases/metabolism ; Oxidoreductases/*urine ; Smoking ; Support, Non-U.S. Gov't ; Theophylline/*pharmacokinetics ; Uric Acid/analogs & derivatives/urine