Effects of renal function on the pharmacokinetics and pharmacodynamics of prophylactic cefazolin in cardiothoracic surgery.

The purpose of this investigation was to study the effects of renal function on the pharmacokinetics and pharmacodynamics (PK-PD) of free cefazolin administered prophylactically in cardiothoracic surgery. Patients received an initial 2-g dose of cefazolin, followed by 1-g doses 6, 12, 18 and 24 h after the first dose. In patients who underwent cardiopulmonary bypass, 1 g was added to the priming solution. In 35 patients with a normal estimated creatinine clearance (CLcr) ≥50 ml/min, a free cefazolin concentration <4 µg/ml was observed in 11.4, 5.7 and 54.3% of patients before the second dose, at the end and 24 h after operation, respectively. In contrast, only 7.4% of 27 patients with CLcr <49 ml/min had a free cefazolin concentration <4 µg/ml 24 h after the operation. There was a high negative correlation between CLcr and time above the target minimal inhibitory concentration (MIC) when the CLcr was <50 ml/min (r(2) = 0.807), and no correlation when the CLcr was ≥50 ml/min. Renal function has a significant impact on the PK-PD of prophylactic cefazolin in cardiothoracic surgery. The postoperative drug dosing intervals should be <6 h in order to achieve a 100% time above the MIC in patients with CLcr ≥ 50 ml/min.

Effects of lansoprazole on pharmacokinetics and metabolism of theophylline.

The effect of the new substituted benzimidizole proton pump inhibitor, lansoprazole, on pharmacokinetics and metabolism of theophylline has been studied in healthy adults given oral lansoprazole 30 mg once daily for 11 days. On Days 4 and 11 of 300 mg aminophylline was simultaneously administered orally and blood samples for theophylline analysis were taken over 24 h. Urine samples were collected for up to 24 h and were assayed for theophylline and its major metabolites 1,3-dimethyluric acid (1,3-DMU), 1-methyluric acid (1-MU) and 3-methylxanthine (3-MX). The pharmacokinetic parameters of theophylline were determined, and the urinary recovery of unchanged theophylline and its major metabolites were calculated. After administration of lansoprazole for 4 days, no significant alteration in the terminal elimination half-life (t1/2beta) or the mean resistance time (MRT) was detected. However, there was a significant decrease of about 13% in the area under the plasma concentration-time curve (AUC) and a significant increase of about 19% in the apparent clearance (CLapp). Lansoprazole treatment for 11 days caused a significant decrease of approximately 12% in t1/2beta and about 10% in the MRT of theophylline, although neither AUC nor CLapp showed a significant alteration. The excretion of 3-MX in the urine was significantly increased by about 20% after lansoprazole treatment for 4 and 11 days, although there was no significant alteration in the excretion of unchanged theophylline, 1,3-DMU or 1-MU. The results indicate that repeated administration of lansoprazole to humans induces the hepatic microsomal P-450-dependent drug oxidation system that mediates N-1-demethylation of theophylline, consequently increasing its metabolism.

Inhibitory effect of diltiazem on diazepam metabolism in the mouse hepatic microsomes.

In order to elucidate the drug interaction between diltiazem and diazepam, the effect of diltiazem on the N-demethylation of diazepam in the mouse hepatic microsomes was investigated. Kinetic study showed that diltiazem noncompetitively inhibited the N-demethylation of diazepam with inhibition constant (Ki) value of 247.8 microM, indicating that diltiazem exhibits an inhibitory effect on the hepatic oxidative metabolism of diazepam. It was therefore suggested that diltiazem may impair the metabolism of diazepam in vivo.