M.Wafik Gouda

Decreased bioavailability of quinidine sulphate due to interactions with adsorbent antacids and antidiarrhoeal mixtures

Abstract The in vitro adsorption of quinidine sulphate on some commercial antacid and antidiarrhoeal preparations was assessed; the effect of some of these admixtures on drug absorption in human bioavailability studies was also measured using salivary secretion data. The adsorption of quinidine on Kaopectate (kaolin-pectin suspension) (25.8 mg/g) and magnesium-trisilicate (23.6 mg/g) was greater than that on Simeco tablets (aluminium hydroxide, magnesium carbonate and hydroxide, simethicone) (5.8 mg/g) or bismuth subnitrate (3.3 mg/g). Salivary quinidine concentrations decreased by 54% and the AUT by 58%, compared with control data, during the quinidine-Kaopectate interaction in vivo. This latter finding suggests a need for clinical monitoring of patients taking quinidine concomitantly with this type of adsorbent-antacid-antidiarrhoeal formulation.

Decreased bioavailability of propranolol due to interactions with adsorbent antacids and antidiarrhoeal mixtures

Abstract The interaction of propranolol (50–160 mg/100 ml) with recommended doses of magnesium trisilicate, kaolin-pectin and bismuth subsalicylate suspensions was studied. Magnesium trisilicate and bismuth subsalicylate were found to adsorb propranolol with a limiting adsorptive capacity of 112 and 97 mg/g, respectively. Kaolin-pectin suspension adsorbed practically all of the drug. The effect of these interactions on the bioavailability of propranolol in rats was determined. The extent, but not the rate. of propranolol absorption was decreased on concomitant administration of the adsorbents. Peak propranolol plasma concentrations decreased by 29245% and a parallel decrease of 35–44% in AUC values was observed. These interactions suggest possible clinically important differences in propranolol bioavailability.

The effect of colestipol and cholestyramine on the systemic clearance of intravenous ibuprofen in rabbits

Abstract— The effect of oral administration of the non‐absorbable anion‐exchange resins cholestyramine and colestipol on the systemic clearance and other pharmacokinetic parameters of intravenously administered ibuprofen (25 mg kg−1) was studied in rabbits. Single doses of colestipol hydrochloride (0·4 g kg−1) or cholestyramine (0·17 g kg−1) were given 30 min before ibuprofen administration. In cholestyramine‐treated rabbits a significant reduction in ibuprofen plasma concentration was observed compared with both control (water only) and colestipol‐treated rabbits. Cholestyramine treatment resulted in a significant decrease in the terminal elimination half‐life and the mean residence time. Furthermore, a 31% increase in the systemic clearance and 23% decrease in the area under the plasma concentration‐time curve were also observed in cholestyramine‐treated rabbits. Colestipol treatment did not change these parameters. The volume of distribution parameters (Vdss and Vdarea) did not change following either treatment. The changes in the pharmacokinetic parameters are compatible with an acceleration of ibuprofen elimination induced by oral administration of cholestyramine and not by colestipol. This effect is thought to be due to augmentation of net biliary excretion through enteric binding.

ACCELERATED CLEARANCE OF INTRAVENOUS INDOMETHACIN BY ORAL ACTIVATED CHARCOAL IN RABBITS

The effect of oral activated charcoal on the systemic clearance and other pharmacokinetic parameters of intravenously administered indomethacin (2 mg /kg) was studied in rabbits. Following a single oral dose of activated charcoal (10 g), a significant reduction in indomethacin serum concentrations was observed. Charcoal treatment resulted m a significant decrease in the terminal elimination half-life (1.26 ± 0.14 and 0.82 ± 0.03 h for the control and treated groups, respectively) and the mean residence time (1.29 ± 0.14 and 0.79 ± 0.03 h for the control and treated groups, respectively). Further, a 68% increase in the systemic clearance (1.92 ± 0.19 and 3.23 ± 0.15 ml/min per kg for the control and treated rabbits, respectively) and 41% decrease in the area under the serum concentration-time curve (17.56 ± 1.82 and 10.34 ± 0.48 μg h/ml in the control and treated groups, respectively) were also noted. Charcoal administration did not significantly alter the volume of distribution (Vc, Vss and Varea). Regarding the microconstants of the two-compartment phannacokinetic model which adequately described indomethacin kinetic in the control and treated rabbits, charcoal administration produced a significant increase in the rate of transfer of indomethacin from the tissue compartment to the central compartment (K21) and out of the central compartment (K10). The results indicate that administration of oral activated charcoal accelerates the systemic elimination of indomethacin. This is presumably mediated by interruption of the enterohepatic circulation of indomethacin by activated charcoal.

Interactions of procainamide, verapamil, guanethidine and hydralazine with adsorbent antacids and antidiarrhoeal mixtures

Abstract The in vitro interactions of procainamide, verapamil, guanethidine and hydralazine with some commercial adsorbent antacids and anti-diarrhoeal preparations were studied. Kaopectate was found to adsorb procainamide, verapamil, guanethidine and hydralazine with a limiting adsorptive capacity of 16.67, 15.15, 9.62 and 20.12 mg/g, respectively, while magnesium trisilicate was found to adsorb the same drugs with a limiting adsorptive capacity of 20.08, 25.13, 33.9 and 100 mg/g respectively. The limiting adsorptive capacity of hydralazine and guanethidine on Pepto-Bismol were 84.03 and 12.5 mg/g while Simeco adsorbed hydralazine with a limited capacity of 26.2 mg/g. Peak salivary procainamide concentration in humans were decreased by about 31% and the AUC was decreased by about (32%) on concurrent administration of kaopectate with the drug. These interactions could lead to important differences in bioavailability of the above drugs.

Effect of an antidiarrhoeal mixture on the bioavailability of tetracycline

Abstract The influence of an antidiarrhoeal mixture, Kaopectate®, on the bioavailability of tetracycline was studied in healthy human subjects. Employing a cross-over design, four subjects in the fasting state were given 250 mg tetracycline HCl as a solution with and without 30 ml Kaopectate®. A drastic and significant decrease (about 50%) in drug absorption resulted. When the antidiarrhoeal mixture was coadministered with a 250 mg capsule, employing a latin-square design with seven subjects, a similar decrease in absorption was observed. The administration of Kaopectate® 2 h before and 2 h after the drug resulted in about 20% decrease in drug absorption.

Interruption of the enterohepatic circulation of indomethacin by cholestyramine in rabbits

Abstract The purpose of this investigation was to determine whether the oral administration of cholestyramine would increase the systemic clearance of indomethacin following intravenous administration (2 mg/kg) to rabbits. In cholestyramine-treated rabbits a significant reduction in indomethacin serum concentration was observed compared to control animals. Cholestyramine treatment resulted in a significant decrease in the terminal elimination half-life (1.26 ± 0.13 and 0.85 ± 0.06 h for the control and treated groups, respectively) and the mean residence time (1.31 ± 0.13 and 0.78 ± 0.04 h for the control and treated rabbits, respectively). Furthermore, a 56% increase in the systemic clearance (1.91 ± 0.17 and 2.99 ± 0.2 ml min −1 kg −1 for the control and treated rabbits, respectively) and 36% decrease in the area under the serum concentration-time curve (17.57 ± 1.62 and 11.19 ± 0.7 μg h ml(su for the control and treated rabbits, respectively) were also observed. Cholestyramine administration did not significantly alter the apparent volume of distribution parameters ( V c , V ss and V area ). Regarding the microconstants of the two-compartment model which adequately described indomethacin kinetic in control and treated rabbits, cholestyramine administration produced a significant increase in the rate of transfer of indomethacin from the tissue compartment (K 21 ) and out of the central compartment ( K 10 ). These findings indicate that cholestyramine administration accelerates the systemic elimination of indomethacin. This effect is thought to be due to augmentation of net biliary excretion through enteric binding.

Effect of acetazolamide on the pharmacokinetics of cyclosporin in rabbits

Abstract The effect of concomitant intravenous administration of acetazolamide on cyclosporins pharmacokinetic parameters has been studied in rabbits. The study design was parallel: the control group of six rabbits received cyclosporin alone, while cyclosporin and acetazolamide were co-administered to six rabbits in the second group. Serial blood samples were collected for 24 h following administration of drugs. Cyclosporin concentrations were determined using a specific monoclonal radioimmunoassay. Pharmacokinetic parameters of cyclosporin were derived using compartmental and non-compartmental techniques. Concomitant administration of acetazolamide with cyclosporin resulted in a significant increase in the terminal elimination half-life of cyclosporin, a significant decrease in cyclosporin total body clearance, and a significant increase in the steady-state volume of distribution relative to the control group. The mean residence time of cyclosporin in the peripheral tissue was dramatically increased with the administration of acetazolamide. The results of this investigation demonstrate a possible interaction between acetazolamide and cyclosporin. The most plausible explanation for this is an alteration in the disposition kinetics of cyclosporin. Adjusting the dose of cyclosporin may be required in patients with uveitis receiving both cyclosporin and acetazolamide.

Effect of sucralfate on procainamide absorption

The possible influence of coadministration of sucralfate on absorption of procainamide was assessed using salivary procainamide concentration. Four healthy volunteers participated in the study, in a randomized crossover fashion. Each subject was randomly assigned to receive either procainamide capsule alone (250 mg) or with sucralfate tablest (1 mg) ingested 12h before procainamide. Cmax was significantly decreased, but only by 5.3% when sucralfate was administered. There was no significant difference between the control and treatment studies for tmax and AUC.

Effects of oral administration of colestipol and cholestyramine on the pharmacokinetics of ketoprofen administered intramuscularly in man

The effect of oral administration of the anion exchange resins colestipol hydrochloride (10 g) or cholestyramine (8 g) on the systemic clearance and other pharmacokinetic parameters of intramuscularly administered ketoprofen (50 mg) has been studied in six healthy male subjects. The study was performed according to a randomized three-way crossover design with a 1 week washout period between each treatment phase. After dosing, serial blood samples were collected for a period of 8 h. Plasma harvested from blood was analyzed for ketoprofen by a sensitive high-performance liquid Chromatographie assay. Cholestyramine administration resulted in a significant reduction in ketoprofen plasma concentrations. No significant differences between colestipol-treated and control groups were observed in the calculated pharmacokinetic parameters (Cl, AUC, Kel, t12 and MRT). Cholestyramine treatment resulted in a significant increase in the Kel (55%, p < 0.01), and Cl (32%, p < 0.005) and a significant decrease in the AUC (24%, p < 0.001), t12 (33%, p < 0.01) and MRT (30%, p < 0.001). These results indicate an enhancement of ketoprofen elimination following cholestyramine administration and a lack of interaction between colestipol and ketoprofen.