Effects of charcoal, sodium bicarbonate, and ammonium chloride on chlorpropamide kinetics.

The effects of activated charcoal, sodium bicarbonate, and ammonium chloride by mouth on chlorpropamide kinetics was studied in six healthy subjects. Activated charcoal, 50 gm, given immediately after 250 mg chlorpropamide reduced its absorption by 90%, but when given in repeated doses from 6 hr on (50 gm followed by 12.5 gm at 6-hr intervals) it did not shorten the chlorpropamide half-life (t 1/2). The t 1/2 of chlorpropamide was shortened from 49.7 +/- 7.4 to 12.8 +/- 1.1 hr by sodium bicarbonate and prolonged to 68.5 +/- 10.5 hr by ammonium chloride. The 72-hr urinary excretion of chlorpropamide was increased fourfold by alkalinization and decreased to 1/20 of baseline by acidification of the urine. The renal clearance of chlorpropamide correlated with urinary pH, ranging from 1 to 1000 ml/hr at the pH from 5 to 8. Urinary pH is likely to explain at least a part of great interindividual differences in the serum chlorpropamide concentrations during steady-state and variations in amount of urinary metabolites. In chlorpropamide intoxications activated charcoal can reduce absorption and alkalinization of the urine accelerates its elimination.

Effect of magnesium hydroxide on the absorption of tolfenamic and mefenamic acids.

The effect of various antacids on the absorption of tolfenamic and mefenamic acids has been investigated in three separate crossover studies, each consisting of four phases. Single doses of magnesium hydroxide (85 mg, 425 mg and 1700 mg) or of water (150 ml) were given by mouth to 6 healthy volunteers immediately after tolfenamic acid 400 mg (Study 1), and, using an identical study design, after mefenamic acid 500 mg (Study 3). In Study 2 sodium bicarbonate 1 g, aluminium hydroxide 1 g, an antacid preparation containing both aluminium and magnesium hydroxides, or water alone were ingested with tolfenamic acid 400 mg. Plasma concentrations of tolfenamic and mefenamic acids and their cumulative excretion in urine were determined up to 24 h. Magnesium hydroxide greatly accelerated, in a dose-dependent manner the absorption of both tolfenamic and mefenamic acids. The peak times in plasma were shortened by about 1 h by 425 mg and 1700 mg magnesium hydroxide, and the peak plasma concentrations of both fenamates were elevated up to 3-fold. The area under the plasma concentration-time curve between 0 and 1 h of tolfenamic acid was increased up to 7-fold and that of mefenamic acid up to 3-fold. The total bioavailability of tolfenamic and mefenamic acids was only slightly increased. Aluminium hydroxide alone and in combination with magnesium hydroxide significantly retarded the absorption and lowered the peak plasma concentration of tolfenamic acid. Sodium bicarbonate had no significant effect on its absorption. The interaction with magnesium hydroxide leads to higher and earlier peak plasma concentrations of the fenamates.(ABSTRACT TRUNCATED AT 250 WORDS)

Activated charcoal and syrup of ipecac in prevention of cimetidine and pindolol absorption in man after administration of metoclopramide as an antiemetic agent.

The effects of activated charcoal and ipecac syrup by mouth on cimetidine and pindolol absorption were studied in seven subjects, who had ingested 20 mg metoclopramide 1 h earlier, and compared with the adsorption capacity of charcoal in vitro. Activated charcoal, 50 g, given 5 min after 400 mg cimetidine + 10 mg pindolol, reduced their absorption by 99% or more, based on AUC0-48h and the 48-h urinary excretion of the drugs. Syrup of ipecac caused emesis on each occasion. On the average, ipecac reduced the absorption of cimetidine and pindolol by 75% and 60%, respectively. Based on studies in vitro it seems probable that the adsorbing capacity of charcoal for cimetidine but not for pindolol will be saturated if 50 g charcoal is given after an overdose of about 100 fold the therapeutic dose. Because the use of ipecac allowed an absorption of the drugs at least 30 fold that allowed by charcoal, the immediate administration of activated charcoal, without preceding lavage or emesis, should be considered in such poisonings where the adsorption capacity of high charcoal doses will not be saturated.

The effect of cholestyramine and activated charcoal on glipizide absorption.

1. The interference of cholestyramine and activated charcoal with the absorption of glipizide was studied. 2. In a cross-over study comprising three phases, single doses of cholestyramine (8 g), activated charcoal (8 g) or water only were given to six healthy volunteers together with a single dose of glipizide. 3. The absorption of glipizide was moderately (29%, P less than 0.01) reduced by cholestyramine and greatly reduced (81%, P less than 0.01) by activated charcoal. 4. If cholestyramine and glipizide are used concomitantly, glipizide should be taken 1-2 h beforehand. In acute glipizide overdosage, activated charcoal can be used to reduce absorption.

Effects of resins and activated charcoal on the absorption of digoxin, carbamazepine and frusemide.

1. The interference of resins and activated charcoal with the absorption of digoxin, carbamazepine and frusemide was studied. 2. In a cross-over study consisting of four phases, single doses of colestipol hydrochloride (10 g), cholestyramine (8 g), activated charcoal (8 g) or water only were given to six healthy volunteers immediately after the simultaneous ingestion of digoxin (0.25 mg), carbamazepine (400 mg) and frusemide (40 mg). Plasma and urine concentrations of the test drugs and the urine volumes were determined up to 72 h. 3. The absorption of digoxin was not reduced by colestipol, moderately (30-40%, P less than 0.05) reduced by cholestyramine and greatly (96%) by charcoal. 4. The absorption of carbamazepine was not decreased by cholestyramine, slightly (10%) by colestipol and greatly (90%) by activated charcoal. 5. The absorption and the diuretic effect of frusemide were significantly diminished by all agents. The bioavailability was reduced by colestipol 80%, by cholestyramine 95% and by activated charcoal 99.5%. 6. The interference with the gastrointestinal absorption of most of the basic drugs by colestipol and cholestyramine seems to be minimal. On the other hand, the resins may seriously impair the absorption of certain acidic drugs, for example frusemide.

Pharmacokinetics of metformin after intravenous and oral administration to man.

The kinetics of 14C-metformin have been studied in five healthy subjects after oral and intravenous administration. The intravenous dose was distributed to a small central compartment of 9.9 +/- 1.61 (X +/- SE), from which its elimination could be described using three-compartment open model. The elimination half-life from plasma was 1.7 +/- 0.1 h. Urinary excretion data revealed a quantitatively minor terminal elimination phase with a half-life of 8.9 +/- 0.7 h. After the intravenous dose, metformin was completely excreted unchanged in urine with a renal clearance of 454 +/- 47 ml/min. Metformin was not bound to plasma proteins. The concentration of metformin in saliva was considerably lower than in plasma and declined more slowly. The bioavailability of metformin tablets averaged 50--60%. The rate of absorption was slower than that of elimination, which resulted in a plasma concentration profile of "flip-flop" type for oral metformin.

Activated charcoal in the treatment of hypercholesterolaemia: dose-response relationships and comparison with cholestyramine.

The dose-response relationship of activated charcoal in reducing serum cholesterol was determined and the effects of charcoal and cholestyramine were compared in patients with hypercholesterolaemia. In a cross-over study 7 patients ingested charcoal 4, 8, 16 or 32 g/day, and finally bran, each phase lasting for 3 weeks. Serum total and LDL-cholesterol were decreased (maximum 29% and 41%, respectively) and the ratio of HDL/LDL-cholesterol was increased (maximum 121%) by charcoal in a dose dependent manner. Ten further patients with severe hypercholesterolaemia ingested daily for 3 weeks, in random order, activated charcoal 16 g, cholestyramine 16 g, activated charcoal 8 g + cholestyramine 8 g, or bran. The concentrations of total and LDL-cholesterol were reduced by charcoal (23% and 29%, respectively), cholestyramine (31% and 39%) and their combination (30% and 38%). The ratio of HDL/LDL-cholesterol was increased from 0.13 to 0.23 by charcoal, to 0.29 by cholestyramine, and to 0.25 by their combination. Serum triglycerides were increased by cholestyramine but not by charcoal. Other parameters, including the serum concentrations of vitamin A, E and 25(OH)D3 remained unaffected. The changes in lipids only partly subsided during the 3-week bran phase. In general, the acceptability by the patients and the efficacy of activated charcoal, cholestyramine and their combination were about equal, but there were individual preferences for particular treatments.

Effect of time interval between food and drug ingestion on the absorption of oxybutynin from a controlled-release tablet.

The effect of time interval between food and drug ingestion on the bioavailability of oxybutynin was investigated in a randomized, three-phase cross-over study in 31 healthy volunteers. The serum concentrations of oxybutynin and the metabolite, N-desethyloxybutynin were measured up to 48 hr after ingestion of a controlled-release 10 mg oxybutynin tablet either in fasting state, 2 hr after breakfast or 1 hr before. The Cmax of both oxybutynin (P < 0.0001) and N-desethyloxybutynin (P < 0.0001) and the AUC0-1 of N-desethyloxybutynin (P < 0.05) were significantly larger when oxybutynin was ingested 2 hr after breakfast, than during the fasting, but the AUC0-1 of oxybutynin remained unchanged. Breakfast ingested 1 hr after oxybutynin did not affect the pharmacokinetic parameters of oxybutynin or N-desethyloxybutynin. The saliva secretion rate decreased slightly more (P < 0.05), when oxybutynin was administered 2 hr after breakfast than during fasting. The effect of food ingestion on the serum concentrations of oxybutynin and N-desethyloxybutynin is expected to have minor clinical significance only. However, ingestion of the controlled-release tablet 1 hr before meal increases the likelihood of obtaining constant drug levels with lower peak concentrations during the dosage interval, and thus ingestion of the controlled-release tablet 0.5-1 hr before food may well improve tolerability and compliance in patients who suffer from adverse reactions.

Effect of cirrhosis of the liver on the pharmacokinetics of chlormethiazole.

The pharmacokinetics of chlormethiazole were studied in eight patients with advanced cirrhosis of the liver and in six healthy volunteers after oral and intravenous administration of the drug. In the patients the systemic bioavailability of oral chlormethiazole was increased about tenfold, whereas its elimination was only slightly retarded. The increased bioavailability was clearly due to decreased first-pass metabolism of chlormethiazole in the cirrhotic liver. The results indicate that chlormethiazole should be used in reduced dosage when given by mouth to patients with cirrhosis of the liver.