Angelo Tesoro

Ceftazidime disposition in acute and stable cystic fibrosis

Ceftazidime disposition after an intravenous dose of 50 mg/kg infused over 20 min was followed in 10 subjects with cystic fibrosis (CF) hospitalized with acute pulmonary exacerbations and in 10 healthy subjects. Serum ceftazidime elimination t½ decreased from 105.3 ± 12.4 min (X̄ ± SD) in controls to 90.0 ± 11.1 min in subjects with CF. Calculated distribution volumes were both larger in subjects with CF. When normalized for body surface area, total body clearance (Cl) was 41.9% greater in the CF group (142.4 ± 16.9 and 100.5 ± 10.3 ml/min/1.73 m2). Normalization for body weight revealed 64.8% greater Cl in subjects with CF. Fraction of dose recovered in urine was of the same order for each group, while renal clearance (ClR) was 40.9% greater in the subjects with CF (130.1 ± 11.4 and 92.7 ± 11.6 ml/min/1.73 m2). Five subjects with CF were restudied while infection‐free 119 to 219 days after the original study day. With the exception of a 10% increase in the volume of distribution at steady state while infection‐free, kinetic parameters were much the same. No changes in Cl or ClR were evident from one study day to the next. Acute pulmonary infection does not appear to alter ceftazidime clearance in CF. The mechanism underlying increased ceftazidime Cl and ClR in CF is not apparent from the present data.

Temporal variation in the disposition of theophylline and its metabolites

The temporal aspects of theophylline disposition are of interest, as there are predictable time‐dependent fluctuations in the pulmonary function of patients with asthma and theophylline serum concentrations may vary throughout a 24‐hour period. We studied the extent to which there are significant temporal changes in theophylline kinetics and the relative contribution of distribution, metabolism, and excretion to this phenomenon. Eight healthy men received an intravenous dose (6 mg/kg) of theophylline at 8 AM and 8 PM at 1‐week intervals. Serum and urine were analyzed for theophylline and its three major metabolites by HPLC. Distribution volumes and total body and nonrenal clearances showed no differences between morning and evening dosing. The elimination rate was 12% greater after morning dosing. Renal clearance was 24% greater after morning dosing and was accompanied by an increased excretion fraction of unchanged theophylline. Based on total urinary metabolite excretion and the metabolite serum AUCs, there was no evidence of time‐dependent variation in theophylline biotransformation. Although theophylline renal clearance is greater after morning dosing, it is only a small fraction of the overall drug elimination and does not change the total body clearance after morning or evening dosing.

Comparison of deferoxamine pharmacokinetics between asymptomatic thalassemic children and those exhibiting severe neurotoxicity

The use of deferoxamine for iron chelation in transfusion‐dependent thalassemia major is limited by serious neurotoxicity (hearing and vision loss). We assessed whether interpatient variability in handling deferoxamine and resultant accumulation of the drug may account for the neurotoxicity. We studied steady‐state deferoxamine pharmacokinetics during intravenous infusion in two groups of patients—one group exhibited severe manifestations of auditory and visual loss and one group was asymptomatic. The groups were matched for age, sex distribution, weight, treatment period, ferritin levels, and hemoglobin levels. Similarly, doses of deferoxamine at the time of the study were not different. Clearance rates were not different between the symptomatic and asymptomatic patients (39.83 ± 4.54 versus 30.66 ± 4.39 ml/min · kg). However, patients who exhibited toxicity received significantly higher daily doses of subcutaneous deferoxamine at the time of diagnosis of neurotoxicity (9.03 ± 0.96 and 5.58 ± 0.61 mg/kg · hr, respectively; p < 0.005). These data suggest that deferoxamine induced neurotoxicity is dose‐dependent and cannot be attributed to accumulation of the drug caused by slower clearance rates.

An HPLC Method for the Determination of Theophylline and Its Metabolites in Serum and Urine

Abstract A urine and a serum assay have been developed to quantitate theophylline and its major metabolites:1,3-dimethyluric acid, 3-methylxanthine and 1-methyluric acid. Reverse phase chromatography follows a serum acetone extraction procedure and a urine anion exchange clean-up procedure. Lower limits of sensitivity are 0.04 μg/ml for serum metabolites and 1 μg/ml for urine metabolites. Both assays are free of interference from endogenous substances. These assays have been tested successfully in pharmacokinetic and metabolic studies of theophylline.

Pharmacokinetic Disposition of the Oral Iron Chelator Deferiprone in the Domestic Pigeon (Columba livia)

ABSTRACT Deferiprone is a bidentate oral iron chelator used for the treatment of iron overload in people. The purpose of this study was to determine the pharmacokinetic disposition of deferiprone in the domestic pigeon (Columba livia) and to compare the results with a previous study in the white leghorn chicken. Deferiprone (DFP) was administered orally as a suspension at a single dose of 50 mg/kg to 10 iron-loaded (IL-DFP) pigeons and 10 non–iron-loaded controls (NIL-DFP). Six NIL-DFP birds were also administered deferiprone intravenously to determine the bioavailability of the drug after a 30-day washout period. To evaluate if deferiprone induces its own metabolism, the pharmacokinetic disposition of the drug was also studied in the IL-DFP group after oral therapy with deferiprone at a dosage of 50 mg/kg q12h for 30 days. For each phase, collected blood was analyzed for deferiprone by high-performance liquid chromatography to develop a plasma concentration versus time curve. Deferiprone was rapidly absorbed from the gastrointestinal tract, with plasma concentrations effective for iron chelation maintained for at least 8 hours after administration in iron-loaded birds. The half-life (mean ± SD) for deferiprone given orally to the IL-DFP and NIL-DFP groups was 2.98 ± 0.85 hours and 3.26 ± 1.25 hours, respectively, and when intravenously administered was 3.79 ± 1.23 hours. The half-life after 30 days of treatment was 3.42 ± 1.18 hours. Oral bioavailability was 44%. This study demonstrated that oral absorption of deferiprone is acceptable, it does not induce its own metabolism, and the drug was widely distributed in the pigeon, as it was in the chicken, with a longer half-life than that reported in mammals. Minor interspecies variations in the pharmacokinetics of deferiprone exist between chickens and pigeons.

Pharmacokinetic Disposition of the Oral Iron Chelator Deferiprone in the White Leghorn Chicken

ABSTRACT Deferiprone is a bidentate oral iron chelator used for the treatment of transfusional iron overload in people. The purpose of this study was to determine the pharmacokinetic disposition of deferiprone in the white leghorn chicken as a potential model upon which to base therapeutic regimens for the treatment of iron storage disease (hemochromatosis) in affected avian species. A suspension of deferiprone (DFP) was administered orally at a single dose of 50 mg/kg to 10 birds that were iron-loaded (IL-DFP) and 10 non–iron-loaded control birds (NIL-DFP). After a 30-day washout period, 5 birds from the NIL-DFP group were used for a bioavailability study of deferiprone administered intravenously at the same dose. Blood samples were collected at varying intervals over a 24-hour period and were analyzed for deferiprone by high-performance liquid chromatography, then plasma concentration versus time curves were developed. Deferiprone was rapidly absorbed from the gastrointestinal tract of the chicken, with plasma concentrations effective for iron chelation in humans (>20 µmol/L) maintained for at least 8 hours after oral dosing. The half-life (mean ± SD) of the orally administered deferiprone in the IL-DFP and NIL-DFP groups was 2.91 ± 0.78 hours and 3.61 ± 0.90 hours, respectively, and was 2.42 ± 0.24 hours for deferiprone administered intravenously. The mean oral bioavailability was 93%. Deferiprone is well absorbed and widely distributed in the chicken, with a longer half-life than reported in mammals.

Metabolic and pharmacokinetic evaluation of a Novel 3-hydroxypyridinone iron chelator, CP502, in the rat

SummaryA recently synthesized 3-hydroxypyridinone derivative with an amido function at the 2-position, CP502 (1, 6-dimethyl-3-hydroxy-4-(1H)-pyridinone-2-carboxy-(N-methyl)-amide hydrochloride), exhibited high in vitro iron chelating potency (pFe3+=21.7). It was targeted as a new iron-chelating candidate for further development in early pre-clinical testing. To evaluate its pharmacokinetics, including oral bioavailability, metabolic and disappearance profiles, studies were conducted in Sprague Dawley male rats. A single 150 mg/kg intravenous and oral dose was given to male Sprague Dawley rats (N=6, B.Wt. 250g). The rats were placed in metabolic cages and fasted overnight before the dosing. Venous blood samples (200 μL per withdrawal) were collected at defined time points before (blank) and up to 28 h post administration. Urine and feces were collected before dosing (blank) and in 24 h intervals up to 72 h post administration. Plasma CP502 concentration versus time profiles were consistent with two-compartment distribution, and the oral bioavailability approached 100%. Total clearance and mean residence time (i.v.) were 1.02 L/kg/h and 1.10 h, respectively. Simultaneous computer fitting yielded VI and Vss estimates of 0.96 L/kg and 1.74 L/kg, respectively. CP502 was mainly excreted unchanged via urine (45.29± 9.40 % of total dose) or as glucuronide (6.46±1.22% of total dose). High iron chelation potential and favorable pharmacokinetic and metabolic profiles indicate that CP502 is a promising candidate for further development.

High-performance liquid chromatographic assays for a second-generation novel oral iron chelator (APCP363) and their application to pharmacokinetic studies in rats

Sensitive and specific HPLC assays for APCP363 in biological matrices (rat plasma, urine and feces) were developed. The recovery of APCP363 ranged from 81.2 to 99.9% in plasma, from 82.1 to 92.8% in urine, and from 65 to 68% in feces. Standard deviations were below 10% for all analyses. The limits of quantitation were 0.1, 10 and 30 microg/ml in plasma, urine and feces, respectively. The HPLC assays, which are the first reports for APCP363 analysis in biological matrices, have been successfully applied to preliminary pharmacokinetic studies in rats. The stool assay is the first non-radiolabeled method for hydroxypyridinones in feces.

Theophylline-7β-d-Ribofuranoside (Theonosine), a New Theophylline Metabolite Generated in Human and Animal Lung Tissue

While assessing the ability of mammalian lung tissue to metabolize theophylline, a new metabolite was isolated and characterized. The metabolite was produced by the microsomal fraction of lungs from several species, including rat, rabbit, dog, pig, sheep and human tissue. Metabolite production was blocked by boiling the microsomal tissue. This new metabolite, theophylline-7β-d-ribofuranoside (theonosine), was confirmed by several spectral methods and by comparison to an authentic synthetic compound. Tissue studies from rats, rabbits, dogs, and humans for cofactor involvement demonstrated an absolute requirement for NADP and enhanced metabolite production in the presence of magnesium ion. It remains to be demonstrated whether theonosine may contribute to the known pharmacological effects of theophylline.