D. W. A. Bourne

Disposition of sulfadimethoxine in swine: Inclusion of protein binding factors in a pharmacokinetic model

Sulfadimethoxine was administered intravenously and orally to five swine. More than 75% of the dose was excreted into urine as the acetyl metabolite with 4–6% excreted unchanged. Plasma and urine data were not consistent when a linear pharmacokinetic model was used to describe the data. Sulfadimethoxine has a high affinity for plasma protein, and the data were subsequently fitted to a nonlinear model, which included saturable protein binding. The choice of a nonlinear model was further supported by a minimum value for the Akaike information criteria. The protein binding constant obtained was 2.8× 104 M−1and the total protein binding site concentration in plasma was 4.6×10−4m. Both values are comparable with in vitrodata. This result suggests that the nonlinear model involving protein binding can be successfully applied to pharmacokinetic data. The apparent biological half-life of Sulfadimethoxine (free and bound) in plasma was 14 hr; however, the half-life of elimination of free drug was 1.25 hr. Following oral administration, all of the dose was absorbed with an apparent absorption half-life of 2.9 hr.

Determination of nitrazepam and temazepam in plasma by high-performance liquid chromatography.

A rapid and simple high-performance liquid chromatographic analysis of nitrazepam in plasma with temazepam as an internal standard is described here. Alternatively, this assay method can also be used to determine temazepam plasma concentrations with nitrazepam as the internal standard. Chloroform was used as an organic solvent for the extraction process. The percentage recoveries of nitrazepam and temazepam were 79% and 85%, respectively. The coefficient of variation of the within-day precision of the assay procedure at a concentration equal to 50 ng/ml of nitrazepam was 2.4% (n = 5), and that for day-to-day precision at the same concentration was 4.7% (n = 5). Calibration curves for nitrazepam and temazepam were linear over their therapeutic ranges. Pharmacokinetic parameters obtained with this method after a single oral dose of 5 mg of nitrazepam in five normal subjects were comparable to results obtained in previous studies.

Comparison of plasma levels of canrenone and metabolites after base hydrolysis in young and elderly subjects following single and multiple doses of spironolactone

SummaryPlasma levels of canrenone and ‘total metabolites’ after base hydrolysis were compared in young and elderly subjects following single and multiple doses of spironolactone. After the initial dose on Day 1, plasma levels of canrenone and ‘total metabolites’ were higher in the young than in the elderly group, and significant differences were found between the two age groups in the AUC for both canrenone and ‘total metabolites’. However, these differences between the two age groups diminished after multiple dosing on Day 8, and the steady state predose plasma levels of canrenone and ‘total metabolites’ were significantly higher in the elderly subjects. The accumulation ratios of canrenone and ‘total metabolites’ were significantly higher in the elderly than in the young subjects. Both canrenone and canrenoic acid were extensively bound to plasma protein, but no differences were found between the two age groups in protein binding. Observed differences in plasma levels after single and multiple dosing between young and old subjects may be consequences of many factors such as 1.) a proportionate shift in metabolism with age; 2.) impaired oral absorption of the parent compound; and/or 3.) altered volume of distribution of the drug.

Pharmacokinetics of canrenone and metabolites after base hydrolysis following single and multiple dose oral administration of spironolactone

SummaryThe pharmacokinetics of canrenone and ‘total metabolites’ after base hydrolysis was studied in eight young volunteers following single and multiple dose oral administration of spironolactone. The plasma levels of canrenone and ‘total metabolites’ were fitted to a two-compartment open model with a first-order absorption process. From our eight normal subjects studied, the harmonic mean of the distributive half-life (t1/2α) of canrenone was found to be 1.66 h, and the harmonic mean of the terminal elimination half-life (t1/2β) to be 22.6 h. Harmonic means of the distributive and elimination half-lives of ‘total metabolites’ after base hydrolysis were 2.48 h and 28.8 h respectively. The accumulation ratio of canrenone was 2.53, whereas that of ‘total metabolites’ was 1.89. Despite the fact that spironolactone has been shown to induce hepatic metabolism of other drugs, no evidence of autoinduction was noted in the present study, as plasma levels of canrenone and ‘total metabolites’ were found to obey a linear two-compartment model with reproducible absorption and disposition after single and multiple doses.

Physiological pharmacokinetic model for the distribution and elimination of tenoxicam

A physiologically based pharmacokinetic model for tenoxicam distribution and excretion in the rat was developed. The drug concentrations in plasma and all the tissues except testis were simulated using flow-limited equations, while testis concentrations were calculated using a membrane-limited passive diffusion equation. The elimination of tenoxicam was described in the model by renal and hepatic (metabolic and biliary) excretion with gastro-intestinal secretion and reabsorption. In order to validate the model, 15 tissue samples, plasma (for free and total concentration), urine and feces samples were collected and assayed by HPLC after i.v. injection of tenoxicam (4.5 mg/kg). Good agreements between simulation and experimental data over a 24-h period following drug administration were obtained for plasma and tissues. The terminal half-life of tenoxicam was 8.8 h in plasma and ranged in tissues from 6.1 h in intestine to 10.6 h in brain. The fraction of free tenoxicam in plasma ranged from 1.2 to 2.1% of the total tenoxicam concentration (5.7-21.9 μ/ml).

Synthesis and characterization of potential tumor scintigraphic agents.

Potential tumor imaging radiopharmaceutical agents have been prepared by attaching a cisplatin derivative to a ligand capable of forming a stable complex with 99mTc. Three new organometallic compounds, with iminodiacetic acid as the 99mTc chelating group and 2,3-diaminopropionamide as the platinum complexing group, have been prepared and characterized. Preliminary biodistribution studies in tumor bearing mice support the utility of this approach.

Effect of caffeine on ceftriaxone disposition and plasma protein binding in the rat

Previous studies have shown that caffeine can affect drug kinetics by altering drug binding to plasma protein, drug absorption, or drug distribution. In this study, the effect of caffeine on the in vivoprotein binding and the disposition of ceftriaxone (a highly protein-bound cephalosporin) were investigated in the rat. Ceftriaxone 100mg/kg and caffeine 20mg/kg were i.v. injected via the tail vein and ceftriaxone in plasma, plasma filtrate, urine, feces, and tissues (brain, heart, kidney, liver, gut, lung, and muscle) was assayed by HPLC with UV detection. The fraction of free ceftriaxone in plasma ranged from 5.6 to 32.8% of total ceftriaxone (3–347 μg/ml) without caffeine and showed no alteration by caffeine. The total amount of ceftriaxone excreted in urine and feces was increased significantly (p<0.05)from 13.1±1.8mg (mean±SD, 54.6% of total) to 15.3 ±1.1 mg (63.8% of total) by caffeine coadministration. The terminal half-life of ceftriaxone in plasma was shortened from 59 to 47 min, and the area under the plasma drug concentration-time curve (AUC)was reduced from 612 to 516 μg hr/ml Although the peak drug concentrations and the times of peak concentration of ceftriaxone in tissues were not altered by caffeine administration, the elimination of ceftriaxone was increased, as indicated by generally shorter half-lives (decreases ranged from 17.5% in liver to 34.2% in brain) and lower AUCvalues (from 9.0% in heart to 54.5% in brain). These results suggest that caffeine does not alter the protein binding of ceftriaxone, but enhances the elimination of ceftriaxone in the rat.

Effect of caffeine on the plasma protein binding and the disposition of ceftriaxone

The effects of caffeine on the in‐vitro protein binding and the pharmacokinetics of ceftriaxone (a highly protein bound cephalosporin) were investigated. Caffeine failed to decrease in‐vitro protein binding of ceftriaxone. Rabbit plasma concentrations of ceftriaxone (30 mg kg−1 i. v.) were elevated significantly (P <005 at 0.3, 0.6 and 1 h after injection) when caffeine 5 or 10 mg kg−1 i.v. was co‐administered compared with ceftriaxone given alone. Caffeine increased the volume of distribution of the central compartment (V1) for ceftriaxone significantly from 49 ± 38 ml kg−1 (mean ± s.d., n = 6) to 97 ± 33 ml kg−1 (caffeine 5 mg kg−1, P <0.05), and 94 ± 8 ml kg−1 (caffeine 10 mg kg−1, P <0.05) and decreased the volume of distribution of the peripheral compartment (V2) from 145 ± 106 ml kg−1 (mean ± s.d., n = 6) to 31 ± 18 ml kg−1 (caffeine 5 mg kg−1, P <0.05) and 36 ± 31 ml kg−1 (caffeine 10 mg kg−1, P < 0.1). The rate of transfer of ceftriaxone to the peripheral compartment (k12) was also decreased significantly (P <0.05) after caffeine. The elevated plasma concentration of ceftriaxone, increased V1 value and the decreased V2 and k12 values are probably the result of caffeine altering the distribution of ceftriaxone to the central and the peripheral compartments.