Pros and cons of insulin administration on liver glucose metabolism in strength-trained healthy mice

Non-diabetic individuals use hormones like insulin to improve muscle strength and performance. However, as insulin also leads the liver and the adipose tissue to an anabolic state, the purpose of this study was to investigate the effects of insulin on liver metabolism in trained non-diabetic Swiss mice. The mice were divided into four groups: sedentary treated with saline (SS) or insulin (SI) and trained treated with saline (TS) or insulin (TI). Training was made in a vertical stair, at 90% of the maximum load, three times per week. Insulin (0.3 U/kg body weight) or saline were given intraperitoneally five times per week. After eight weeks, tissue and blood were collected and in situ liver perfusion with glycerol+lactate or alanine+glutamine (4 mM each) was carried out. The trained animals increased their muscle strength (+100%) and decreased body weight gain (-11%), subcutaneous fat (-42%), mesenteric fat (-45%), and peritoneal adipocyte size (-33%) compared with the sedentary groups. Insulin prevented the adipose effects of training (TI). The gastrocnemius muscle had greater density of muscle fibers (+60%) and less connective tissue in the trained groups. Liver glycogen was increased by insulin (SI +40% and TI +117%), as well as liver basal glucose release (TI +40%). Lactate and pyruvate release were reduced to a half by training. The greater gluconeogenesis from alanine+glutamine induced by training (TS +50%) was reversed by insulin (TI). Insulin administration had no additional effect on muscle strength and reversed some of the lipolytic and gluconeogenic effects of the resistance training. Therefore, insulin administration does not complement training in improving liver glucose metabolism.

Effect of cardiopulmonary bypass on the pharmacokinetics of propranolol and atenolol

The pharmacokinetics of some β-blockers are altered by cardiopulmonary bypass (CPB). The objective of this study was to compare the effect of coronary artery bypass graft (CABG) surgery employing CPB on the pharmacokinetics of propranolol and atenolol. We studied patients receiving oral propranolol with doses ranging from 80 to 240 mg (N = 11) or atenolol with doses ranging from 25 to 100 mg (N = 8) in the pre- and postoperative period of CABG with moderately hypothermic CPB (32°C). On the day before and on the first day after surgery, blood samples were collected before β-blocker administration and every 2 h thereafter. Plasma levels were determined using high-performance liquid chromatography and data were treated by pharmacokinetics-modelling. Statistical analysis was performed using ANOVA or the Friedman test, as appropriate, and P < 0.05 was considered to be significant. A prolongation of propranolol biological half-life from 5.41 ± 0.75 to 11.46 ± 1.66 h (P = 0.0028) and an increase in propranolol volume of distribution from 8.70 ± 2.83 to 19.33 ± 6.52 L/kg (P = 0.0032) were observed after CABG with CPB. No significant changes were observed in either atenolol biological half-life (from 11.20 ± 1.60 to 11.44 ± 2.89 h) or atenolol volume of distribution (from 2.90 ± 0.36 to 3.83 ± 0.72 L/kg). Total clearance was not changed by surgery. These CPB-induced alterations in propranolol pharmacokinetics may promote unexpected long-lasting effects in the postoperative period while the effects of atenolol were not modified by CPB surgery.

Cardiopulmonary bypass alters the pharmacokinetics of propranolol in patients undergoing cardiac surgery

The pharmacokinetics of propranolol may be altered by hypothermic cardiopulmonary bypass (CPB), resulting in unpredictable postoperative hemodynamic responses to usual doses. The objective of the present study was to investigate the pharmacokinetics of propranolol in patients undergoing coronary artery bypass grafting (CABG) by CPB under moderate hypothermia. We evaluated 11 patients, 4 women and 7 men (mean age 57 ± 8 years, mean weight 75.4 ± 11.9 kg and mean body surface area 1.83 ± 0.19 m²), receiving propranolol before surgery (80-240 mg a day) and postoperatively (10 mg a day). Plasma propranolol levels were measured before and after CPB by high-performance liquid chromatography. Pharmacokinetic Solutions 2.0 software was used to estimate the pharmacokinetic parameters after administration of the drug pre- and postoperatively. There was an increase of biological half-life from 4.5 (95 percent CI = 3.9-6.9) to 10.6 h (95 percent CI = 8.2-14.7; P < 0.01) and an increase in volume of distribution from 4.9 (95 percent CI = 3.2-14.3) to 8.3 l/kg (95 percent CI = 6.5-32.1; P < 0.05), while total clearance remained unchanged 9.2 (95 percent CI = 7.7-24.6) vs 10.7 ml min-1 kg-1 (95 percent CI = 7.7-26.6; NS) after surgery. In conclusion, increases in drug distribution could be explained in part by hemodilution during CPB. On the other hand, the increase of biological half-life can be attributed to changes in hepatic metabolism induced by CPB under moderate hypothermia. These alterations in the pharmacokinetics of propranolol after CABG with hypothermic CPB might induce a greater myocardial depression in response to propranolol than would be expected with an equivalent dose during the postoperative period.

A micromethod for quantitation of debrisoquine and 4-hydroxydebrisoquine in urine by liquid chromatography

We describe a new simple, selective and sensitive micromethod based on HPLC and fluorescence detection to measure debrisoquine (D) and 4-hydroxydebrisoquine (4-OHD) in urine for the investigation of xenobiotic metabolism by debrisoquine hydroxylase (CYP2D6). Four hundred µl of urine was required for the analysis of D and 4-OHD. Peaks were eluted at 8.3 min (4-OHD), 14.0 min (D) and 16.6 min for the internal standard, metoprolol (20 µg/ml). The 5-µm CN-reverse-phase column (Shimpack, 250 x 4.6 mm) was eluted with a mobile phase consisting of 0.25 M acetate buffer, pH 5.0, and acetonitrile (9:1, v/v) at 0.7 ml/min with detection at lexcitation = 210 nm and lemission = 290 nm. The method, validated on the basis of measurements of spiked urine, presented 3 ng/ml (D) and 6 ng/ml (4-OHD) sensitivity, 390-6240 ng/ml (D) and 750-12000 ng/ml (4-OHD) linearity, and 5.7/8.2 percent (D) and 5.3/8.2 percent (4-OHD) intra/interassay precision. The method was validated using urine of a healthy Caucasian volunteer who received one 10-mg tablet of Declinax®, po, in the morning after an overnight fast. Urine samples (diuresis of 4 or 6 h) were collected from zero to 24 h. The urinary excretion of D and 4-OHD, Fel (0-24 h), i.e., fraction of dose administered and excreted into urine, was 6.4 percent and 31.9 percent, respectively. The hydroxylation capacity index reported as metabolic ratio was 0.18 (D/4-OHD) for the person investigated and can be compared to reference limits of < 12.5 for poor metabolizers (PM) and < 12.5 for extensive metabolizers (EM). In parallel, the recovery ratio (RR), another hydroxylation capacity index, was 0.85 (4-OHD: SD + 4-OHD) versus reference limits of RR < 0.12 for PM and RR > 0.12 for EM. The healthy volunteer was considered to be an extensive metabolizer on the basis of the debrisoquine test.