Seromucosal Transport of Intravenously Administered Carbamazepine Is Not Enhanced by Oral Doses of Activated Charcoal in Rats

Abstract

Abstract:The fate of carbamazepine after intravenous injection in rats (n = 24) and the influence of activated charcoal on the kinetics was investigated. After randomization to four groups (n = 6, each), plasma concentration and the quantities of carbamazepine and metabolites excreted into bile, urine and intestine were determined using an in situ perfusion model of the small intestine (Ringer's solution) with or without orally administered activated charcoal (AC + ; AC-) and with or without bile duct cannulation (BD + ; BD -). The cumulative amount of carbamazepine and metabolites exsorbed into the small intestine within 3.5 hr after intravenous injection was about 15% in BD -animals and about 3% in BD + animals. About 20% of the dose was detected in the externalized bile. Activated charcoal did not influence the amount exsorbed into the small intestine. Terminal half-life in plasma ranged from 159 min. to 194 min. within the four treatment groups without statistical significant difference (P = 0.751). Correspondingly, the area under the curve did not vary significantly and ranged between 1.13 and 1.41 g/min./l (P = 0.378). Excretion of carbamazepine and metabolites into urine varied between 3% and 6% of dose within all groups and showed close correlation with diuresis. In an identical experimental approach using a 2-fold intestinal perfusion rate (50 ml/hr; n = 8), no fundamental changes compared to the main experiment regarding pharmacokinetics of carbamazepine were observed. The lack of effect of activated charcoal on the elimination of carbamazepine and metabolites must be contributed to the small amount of the drug being exsorbed into the intestine and may be further influenced by reduced intestinal permeability of carbamazepine and metabolites or inadequate luminal stirring.Activated charcoal is a widely used and generally accepted agent to prevent the absorption of orally ingested drugs, especially in the overdose setting. Although there are no satisfactorily designed clinical studies assessing the benefit from single-dose activated charcoal to recommend this therapy [1], data from literature clearly support the use of multipledose activated charcoal for some toxins such as carbamazepine, dapson, phenobarbital, quinine and theophylline in the case of overdose [2]. Besides the prevention of drug absorption and the possibility of activated charcoal interrupting the enteroenteric circulation, oral administration has also been demonstrated to enhance the clearance of intravenously administered drugs that are exsorbed seromucosally into the intestinal lumen in rats [3][4][5][6][7][8][9][10][11][12]. This process is generally called 'gastrointestinal dialysis' since it was first described in 1982 [13]. Basic pharmacokinetic requirements for clinically relevant seromucosal transport include small size of molecule, intermediate lipophilicity, low protein binding and a small volume of distribution.If a relevant amount of drug would be exsorbed into the intestinal lumen and if orally administered activated charcoa...

The Use of Activated Charcoal to Treat Intoxications

“…Activated charcoal adsorbs many noxious substances-medical drugs, phytotoxins and poisonous chemicals-onto its surface, preventing their absorption from the gastrointestinal tract. As a secondary decontamination mechanism, it interrupts a potential enterohepatic and/or enteroenteric circulation (8,15,16). The capacity for binding to the toxic substance depends on several factors, including (17-19):…”

“…In these circumstances the intestinal wall functions as a semipermeable membrane: toxins can diffuse out of the blood from serosal to mucosal onto the charcoal in the intestinal lumen. These substances usually have a long half-life, a low distribution volume, and low plasma protein binding (11,15,16). The efficacy of multi-dose administration of activated charcoal against severe intoxication with carbamazepine, quinine, phenobarbital, and theo phylline has been demonstrated clinically and/or in animal experiments (11).…”