Disposition of cefotaxime and its metabolite, desacetylcefotaxime, in rat: Application of a pharmacokinetic-protein binding model

1. The pharmacokinetics and protein binding of cefotaxime and desacetylcefotaxime were studied in rat. 2. After i.v. dosing of cefotaxime (100mg/kg) the concentration-time profiles of cefotaxime and its metabolite desacetylcefotaxime followed biphasic decays, giving the kinetic parameters for cefotaxime: VT ss and AUC of 127ml/kg and 8.2mg/min per ml, respectively. The elimination half-life was 17 min with Cls of 13.1 ml/min per kg. The average association constant (K x 103M-1) and total protein binding site concentration (Pt x 10-3M) for cefotaxime were 3.87 and 0.68, respectively, with saturation of plasma protein binding occurring at about 30 μg/ml. The average free fraction of cefotaxime in plasma (Fp) was 0.48. 3. The metabolite desacetylcefotaxime had a plasma Cmax of 74.4μg/ml (35 min). The respective elimination half-life and AUC were 53 min and 7.2 mg/min per ml. The binding profile, unlike that of cefotaxime, was non-saturable with a K value of 13.90M-1. The Fp of desacetylcefotaxime was 0.89. 4. The concentration-time behaviour of total and free desacetylcefotaxime (i.v. bolus, 50mg/kg) declined biexponentially with respective VTss and AUC of 125ml/kg and 19.4 mg/min per ml (total drug), and 192 ml/kg and 13.9 mg/min per ml (free drug). The phase half-life of total and free drug was about 36 min, whereas CLs (ml/min per kg) were 2.7 (total) and 3.7 (free). The binding characteristics were in good agreement with those of the metabolite produced in vivo, with a K value of 8.58M-1. The Fp value of desacetylcefotaxime in plasma was 0.73

Disposition of ceftriaxone in rat: Application of a pharmacokinetic-protein binding model and comparison with cefotaxime

1. The pharmacokinetic profile and protein binding parameters of ceftriaxone were determined in rat, and compared with those of cefotaxime. 2. Plasma concentration-time curves of ceftriaxone and cefotaxime (single i.v. bolus; 100mg/kg each) were described by a two-compartment, protein-binding model. 3. The corrected VT ss(ml/kg) of ceftriaxone was lower than that of cefotaxime. The AUCs of both drugs were similar. The t1/2 of the two drugs differed significantly, being 29min for ceftriaxone and 17min for cefotaxime. 4. In vivo protein binding constants of both drugs were similar, but the concentrations of protein binding sites differed significantly. The average free fractions in plasma (Fp) of ceftriaxone and cefotaxime were 0.22 and 0.48 respectively. 5. Saturation of the binding site for cefotaxime was estimated to occur at about 30 μg/ml in plasma, whereas saturation for ceftriaxone was seen at lower concentrations

High-performance liquid chromatographic method for the quantitation of bupivacaine, 2,6-pipecoloxylidide and 4′-hydroxybupivacaine in plasma and urine

A high-performance liquid chromatographic method with ultraviolet detection at 210 nm for quantitation of bupivacaine and two of its metabolites from plasma and urine is described. The compounds are extracted into n-hexane-isopropanol (5:1), evaporated and the reconstituted residue injected onto a reversed phase C18 column. Standard curves for all compounds were linear (r2 > 0.999) in the range 20-2000 ng/ml, with a limit of detection of 10 ng/ml. The inter-day coefficients of variation ranged between 2.7 and 12.2%. The method was applied to analyse bupivacaine and metabolite concentrations in patients on long-term epidural bupivacaine-fentanyl infusions

The pharmacokinetics of amiloride-hydrochlorothiazide combination in the young and elderly

The pharmacokinetics of amiloride and hydrochlorothiazide were studied in 12 healthy young volunteers following a single dose of a fixed combination of amiloride and hydrochlorothiazide and in 11 elderly hypertensive patients at steady-state. Following modelling of the single dose data, simulated steady-state plasma concentrations for the 2 drugs were generated to examine the effect of age and/or hypertension on pharmacokinetics. The apparent systemic plasma clearance for both amiloride and hydrochlorothiazide was significantly reduced in the elderly when compared to the young (from 753 to 325 ml.min-1, amiloride; and from 418 to 157 ml.min-1, hydrochlorothiazide). The plasma concentrations at steady state for both drugs were greatly increased in the elderly patients (Amiloride: from 7 to 25 ng.ml-1, Css,max; from 2 to 8 ng.ml-1, Css,min; and from 4 to 14 ng.ml-1, Cav; Hydrochlorothiazide: from 184 to 651 ng.ml-1, Css,max; from 31 to 121 ng.ml-1, Css,min; and from 89 to 273 ng.ml-1, Cav). The decreased clearance of the diuretics in the elderly was believed due to deterioration of renal function, and there was a significant correlation between the plasma clearance of hydrochlorothiazide and creatinine clearance in both age groups (r = 0.62, young; r = 0.72, elderly). As a result of the pharmacokinetic findings caution may be indicated in the clinical dosage of the diuretics particularly when in fixed dose combination

Interpleural bupivacaine infusion compared with intravenous pethidine infusion after cholecystectomy

Twenty-six cholecystectomy patients received either an interpleural infusion of bupivacaine (Group B, n = 12) or an intravenous infusion of pethidine (Group P, n = 14) for management of postoperative pain over a three-day period. Patients in Group P experienced a significantly (P less than 0.05) greater incidence of total side-effects (146) than patients in Group B (66). Pain scores (VAS) and responses to a pain questionnaire were similar for both groups; however, within Group B improvement in mean VAS scores at rest with time were more sustained. Similar reductions in FEV1 and FVC from preoperative values occurred for both groups, while for Group P there were significant (P less than 0.05) changes in arterial blood gases (increase in PCO2, decrease in PO2) over two days postoperatively. Patients in Group P recorded longer times to passing flatus and unaided mobilisation (P less than 0.05), and required a significantly greater number of additional medications (anti-emetics and analgesics) over the postoperative period (41 vs 29, P less than 0.05)

Pharmacokinetics of alcuronium in elderly patients undergoing total hip replacement or aortic reconstructive surgery

The pharmacokinetic behaviour of alcuronium was studied in three patients undergoing resection of an aortic aneurysm, and in another two patients undergoing total hip replacement (group I). A control group of five elderly patients undergoing relatively minor surgery was included (group II). In group I patients, the values of the pharmacokinetic parameters such as plasma clearance, elimination half-life and the apparent volume of distribution of the drug were found to be comparable to those obtained in normal young patients in previous studies. The group II patients, however, were found to have a prolonged elimination half-life as a result of reduced plasma clearance, possibly an age-related effect. The differences between those two groups of patients may be explained by the differences in the extent of haemorrhage and fluid replacement or changes in blood circulation, or both. However, alcuronium must still be used cautiously in both groups of patients, especially in the light of a recent finding that patients undergoing aortic reconstructive surgery have a high frequency of functional renal failure after operation