Oral phosphate binders: phosphate binding capacity of iron (III) hydroxide complexes containing saccharides and their effect on the urinary excretion of calcium and phosphate in rats.

Phosphate binders that contain aluminum or calcium are frequently prescribed to treat hyperphosphatemia in patients with end-stage renal disease (ESRD), but an accumulation of aluminum can lead to encephalopathy, aluminum-related bone disease (ARBD) such as osteomalacia, anaemia, and resistance to erythropoietin, and calcium accumulation can lead to hypercalcaemia. High phosphate concentrations are reduced in vitro and in vivo by a phosphate adsorption pill, which is synthesized by hydrolyzing ferrous sulfate in the presence of saccharides, to form an iron (III)-saccharide complex that is acid resistant and binds phosphate greater than iron (III) hydroxide alone. Under in vitro conditions, containing 3.26 mg P/dL, the iron (III)-sucrose complex showed the highest phosphate adsorption capacity at pH 2 with artificial gastric juice, 58.9 mg P/g binder. For the 7 day in vivo study, 0% (Group 1), 1% (Group 2), 4% (Group 3), and 8% (Group 4) iron (III)-sucrose complex was admixed into the rodent chow by weight and fed to 15 male Wistar rats. The weight and volume of the feces and urine, and the calcium, iron, and phosphorus excretions in the feces and urine samples were monitored for any signs of irregularity. Total urine outflow was collected during a 24-h period to determine the amount of phosphate recovered, which indicates the ability of the phosphate binder to reduce gastrointestinal phosphate absorption. The fecal iron excretion was significantly effected by the amount of binder ingested throughout the study for Group 2 (p < 0.001), Group 3 (p < 0.01), and Group 4 (p < 0.001). The urinary calcium excretion (mg/rat/24-h) significantly increased by the 7th day for Group 2 (p < 0.05) and Group 4 (p < 0.01) in comparison to the control. Finally, after 7 days, there was a significant drop in the urinary phosphorus levels (mg P/rat/24-h) in a dose dependent manner for Group 2: from 7.82 +/- 1.46 to 1.98 +/- 0.10 mg P/rat/24-h (102 mg P/dL/24-h; p < 0.05); Group 3: from 6.70 +/- 1.14 to 0.16 +/- 0.09 mg P/rat/24-h (6.0 mg P/dL/24-h; p < 0.01); and Group 4: from 8.25 +/- 0.67 to 0.04 +/- 0.01 mg P/rat/24-h (0.9 mg P/dL/24-h; p < 0.01). The results show that this new adsorbent might provide an alternative to conventional aluminum and calcium containing phosphate-binding agents for combating hyperphosphataemia.

Metabolism and excretion of a new anxiolytic drug candidate, CP-93, 393, in healthy male volunteers.

CP-93,393 [(7S,9aS)-1-(2-pyrimidin-2-yloctahydropyrido[1,2-a] pyrazin-7-ylmethyl)pyrrolidine-2,5-dione] is a new anxiolytic drug with highly selective serotonin 5-hydroxytryptamine 1A autoreceptor agonist, alpha2-adrenergic antagonist, and dopamine D2 agonist properties. The excretion, biotransformation, and pharmacokinetics of CP-93,393 were investigated in six healthy male volunteers after oral administration of a 5-mg dose of [14C]CP-93,393. The administered radioactivity was excreted predominantly in the urine. One week after administration of the dose, cumulative excretion amounted to 67.8 +/- 2.5% in the urine and 22.0 +/- 5.6% in the feces. In total, 89.8 +/- 5.7% of the radioactive dose was recovered in urine and feces. Mean maximum plasma concentration values for unchanged CP-93,393 were 10.92 and 1.02 ng/ml for poor metabolizers (PMs) and extensive metabolizers (EMs) of dextromethorphan, respectively. AUC0-infinity values for unchanged CP-93,393 were also greater for PMs than for EMs, whereas the mean maximum plasma concentration and AUC0-infinity values for total radioactivity were similar for the two phenotypes. Less than 0.5% of the dose was excreted in urine as unchanged drug for both EMs and PMs, suggesting extensive metabolism of CP-93,393 in both phenotypes. Hydroxylation at the 5-position of the pyrimidine ring was identified as the main metabolic pathway. 5-Hydroxy-CP-93,393 (M-15) and its glucuronide and sulfate conjugates (M-7 and M-13, respectively) accounted for approximately 51% of the administered dose in excreta of both PMs and EMs. Hydrolysis of the succinimide ring, in combination with 5-hydroxylation and/or conjugation or not, accounted for approximately 9% of the dose. A novel metabolite, apparently resulting from oxidative degradation of the pyrimidine ring, was characterized as the amidine analog M-18. M-15 (47-62%), its sulfate conjugate (M-13, approximately 9%), and the pyrimidine ring-cleaved product (M-18, 7-13%) were identified as the major circulating metabolites for both EMs and PMs. Therefore, CP-93,393 undergoes metabolism by three primary pathways, i.e. 1) aromatic hydroxylation followed by conjugation with glucuronic acid and sulfuric acid, 2) oxidative degradation of the pyrimidine ring, and 3) hydrolysis of the succinimide ring. The identified metabolites accounted for approximately 90, 91, and 92% of the total radioactivity present in urine, plasma, and feces, respectively. The major in vivo oxidative metabolites were also observed after in vitro incubations with human liver microsomes.

The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data.

We describe a comprehensive retrospective analysis in which the abilities of several methods by which human pharmacokinetic parameters are predicted from preclinical pharmacokinetic data and/or in vitro metabolism data were assessed. The prediction methods examined included both methods from the scientific literature as well as some described in this report for the first time. Four methods were examined for their ability to predict human volume of distribution. Three were highly predictive, yielding, on average, predictions that were within 60% to 90% of actual values. Twelve methods were assessed for their utility in predicting clearance. The most successful allometric scaling method yielded clearance predictions that were, on average, within 80% of actual values. The best methods in which in vitro metabolism data from human liver microsomes were scaled to in vivo clearance values yielded predicted clearance values that were, on average, within 70% to 80% of actual values. Human t1/2 was predicted by combining predictions of human volume of distribution and clearance. The best t1/2 prediction methods successfully assigned compounds to appropriate dosing regimen categories (e.g., once daily, twice daily and so forth) 70% to 80% of the time. In addition, correlations between human t1/2 and t1/2 values from preclinical species were also generally successful (72-87%) when used to predict human dosing regimens. In summary, this retrospective analysis has identified several approaches by which human pharmacokinetic data can be predicted from preclinical data. Such approaches should find utility in the drug discovery and development processes in the identification and selection of compounds that will possess appropriate pharmacokinetic characteristics in humans for progression to clinical trials.

Pharmacokinetic and metabolic aspects of the moclobemide-food interaction.

The effect of a protein-rich meal on the pharmacokinetics of moclobemide was studied after intravenous (75 mg) and oral (100 mg) administrations of this selective MAO-A inhibitor to eight healthy male volunteers. The meal chosen did not affect plasma concentration-time curves of the drug after oral administration apparently, because the influence of blood flow changes to the liver on hepatic first-pass metabolism (AUC increases) and on systemic clearance (AUC decreases) balance each other out.

Free drug concentration monitoring in clinical practice. Rationale and current status.

Recent advances in techniques to determine free drug concentrations have lead to a substantial increase in the monitoring of this parameter in clinical practice. The majority of drug binding to macromolecules in serum can be accounted for by association with albumin and alpha 1-acid glycoprotein. Albumin is the primary binding protein for acidic drugs, while binding to alpha 1-acid glycoprotein is more commonly observed with basic lipophilic agents. Alterations in the concentrations of either of these macromolecules can result in significant changes in free fraction. Diseases such as cirrhosis, nephrotic syndrome and malnourishment can result in hypoalbuminaemia. Burn injury, cancer, chronic pain syndrome, myocardial infarction, inflammatory diseases and trauma are all associated with elevations in the concentration of alpha 1-acid glycoprotein. Treatment with a number of drugs has also been shown to increase alpha 1-acid glycoprotein serum concentrations. A wide variety of biological fluids have been examined for their ability to provide an estimation of free drug concentration at receptor sites. The most useful fluid for estimating free drug concentrations appears to be plasma or serum, with subsequent treatment of the sample to separate free and bound drug by an appropriate technique. The two most widely used methods are equilibrium dialysis and ultrafiltration. Of these two, ultrafiltration has the greatest utility clinically because it is rapid and relatively simple. The major difficulty associated with this method involves the binding of drug to the ultrafilters, but significant progress has been made in solving this problem. Several authors have endorsed the routine use of free drug concentration monitoring. Data examining the clinical usefulness of free drug concentration monitoring for phenytoin, carbamazepine, valproic acid, disopyramide and lignocaine (lidocaine) are reviewed. While available evidence suggests that free concentrations may correlate with clinical effects better than total drug concentrations, there are insufficient data to justify the recommendation of the routine use of free drug concentration monitoring for any of these agents at present.

Pharmacokinetics of ketoconazole administered intravenously to dogs and orally as tablet and solution to humans and dogs.

The single-dose pharmacokinetics and bioavailability of three ketoconazole formulations were evaluated using HPLC in five healthy human volunteers and six male mongrel dogs. The human volunteers received 400 mg po of ketoconazole as tablet (Ktab) and solution (Ksol) formulations. The dogs received 400 mg po of Ktab and Ksol, and 376 mg iv of an intravenous dose (Kiv). In humans the AUC value for Ksol (62.21 +/- 21.2 microgram X h/ml; mean +/- SD) was significantly greater than for Ktab (50.0 +/- 15.2 micrograms X h/ml; p less than 0.05). Peak serum concentrations (Cmax), time to peak serum concentrations (tmax), t1/2, and the terminal elimination rate constant (kel) did not differ between Ktab and Ksol. This suggests that the administration of Ksol may be a useful alternative to dosage increases in situations where low bioavailability of ketoconazole in tablet form is suspected. The mean systemic clearance (CLs) of Kiv in dogs was 2.74 +/- 1.10 mL/min/kg, the volume of distribution at steady state (Vdss) was 0.72 +/- 0.28 L/kg, and the half-life was 2.7 +/- 1.6 h. Considerable variability was seen in the AUC of ketoconazole, particularly with the oral preparations. The absolute bioavailability of Ktab was 0.50 +/- 0.38, which did not differ statistically from that of Ksol, 0.56 +/- 0.23. The Ksol showed less variability in AUC, Cmax, and F values than did Ktab, and two dogs with low bioavailability with Ktab (0.04 and 0.07) had substantially greater bioavailability with Ksol (F = 0.96 and 0.57, respectively). Evaluation of Kiv in dogs confirms decreased bioavailability from orally administered tablet formulations of ketoconazole.

Clinical risk factors for prolonged PT/PTT in abdominal sepsis patients treated with moxalactam or tobramycin plus clindamycin.

Factors associated with prolongation of the prothrombin time were analyzed in 94 patients with intra-abdominal sepsis. Patients were randomized prospectively to receive either the combination of tobramycin and clindamycin (TM/C) or moxalactam (MOX). This paper presents a retrospective review designed to compare the frequency of prolonged clotting times and to analyze predisposing factors. Prothrombin time (PT) prolongation occurred more frequently in patients given moxalactam (19 of 47 patients) than in patients given the combination of tobramycin and clindamycin (9 of 47 patients) (p less than 0.05). Prolongation of the partial thromboplastin time (PTT) occurred in all patients with a prolonged PT. Liver disease, upper gastrointestinal surgery, and use of cimetidine were more frequent in those patients with abnormal PT/PTT values (p less than 0.05). Two moxalactam-treated patients with subsequent PT/PTT prolongation had individual clotting factors assayed before moxalactam treatment and at the time of detection of the abnormal PT. The activity of clotting factors II, VII, VIII, IX, X, and XII was reduced during MOX therapy. Treatment with vitamin K reversed the abnormality. In view of underlying abnormalities and rapid response to parenteral vitamin K, the mechanism is probably an acute vitamin K deficiency superimposed upon chronic vitamin K deficiency. In patients with intra-abdominal infection, those treated with MOX are more likely to develop abnormal PT than those treated with TM/C. Since abnormal PT/PTT was common even in TM/C patients, supplemental vitamin K should be considered for all seriously ill, older patients with abdominal infections.