Effect of activated charcoal alone or given after gastric lavage in reducing the absorption of diazepam, ibuprofen and citalopram

O. Lapatto-Reiniluoto, K. T. Kivisto & P. J. Neuvonen

Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

Aims The ecacy of activated charcoal alone, and gastric lavage followed by charcoal in reducing the absorption of diazepam, ibuprofen and citalopram was studied in healthy volunteers. Methods In a randomized cross-over study with three phases, nine healthy volunteers were administered single oral doses of 5 mg diazepam, 400 mg ibuprofen and 20 mg citalopram, taken simultaneously after an overnight fast. Thirty minutes later, the subjects were assigned to one of the following treatments: 200 ml water (control), 25 g activated charcoal as a suspension in 200 ml water or gastric lavage followed by 25 g charcoal in suspension given through the lavage tube. Plasma concentrations of diazepam, ibuprofen and citalopram were determined up to 10 h. Results The AUC(0,10 h) of diazepam was reduced by 27% ( P<0.05) by both charcoal alone and charcoal combined with lavage. The increase in plasma diazepam concentration from 0.5 h onwards was prevented by both interventions ( P0.05), whereas the Cmax of diazepam was not signicantly aected by either treatment. The AUC(0, 10 h) of ibuprofen was reduced by 49% ( P<0.05) after the combination treatment and by 30% ( P<0.05) after charcoal alone, but there was no signicant dierence between these two treatments. Both charcoal alone and the combination treatment were equally eective in preventing the increase in plasma ibuprofen from 0.5 h onwards ( P<0.01). The Cmax of ibuprofen was reduced by 45% ( P<0.05) and by 21% ( P=NS), respectively. The AUC(0,10 h) of citalopram was reduced by 51% ( P<0.05) after both charcoal alone and charcoal combined with lavage, and the Cmax by 52% ( P<0.05) and 54% ( P<0.05), respectively. The increase in plasma citalopram concentration from 0.5 h onwards was reduced by about 50% ( P<0.01) by both interventions. Conclusions Activated charcoal alone and charcoal combined with lavage showed similar ecacy in preventing the absorption of diazepam, ibuprofen and citalopram. These results suggest that gastric lavage needs not be routinely performed before administration of charcoal. Keywords: charcoal, citalopram, diazepam, gastric lavage, ibuprofen

Introduction
In the management of self-poisoned patients, gastric lavage is routinely performed in many centres before activated charcoal is administered. However, there has long been controversy in the medical literature concerning the ecacy of gastric lavage [1, 2]. It seems to remove only a small proportion of ingested drug if it
Correspondence: Dr Outi Lapatto-Reiniluoto, Department of Clinical Pharmacology, University of Helsinki, Haartmaninkatu 4, FIN-00290 Helsinki, Finland. Received 30 November 1998, accepted 14 April 1999.

is not performed soon after overdose, and clinical studies suggest that, in most cases, performing gastric lavage before administration of charcoal does not inuence clinical outcome [3, 4]. However, to our knowledge, a comparison between the ecacy of lavage combined with charcoal and charcoal alone in preventing drug absorption under controlled conditions has not been previously made. The aim of the present study was to compare the eectiveness of gastric lavage followed by administration of activated charcoal and charcoal alone in reducing drug absorption. Diazepam, ibuprofen and citalopram were
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Effect of gastric decontamination on absorption of diazepam, ibuprofen and citalopram

chosen as test drugs, since they are commonly used and dier in rate of absorption. Furthermore, the eect of gastric decontamination on the absorption of these drugs seems not to have been previously studied.

three phases of the study without any adverse eect related either to the treatments or drugs studied.

Blood sampling and assay of drugs

A forearm vein of each subject was cannulated with a plastic cannula and kept patent with an obturator. Timed blood samples (10 ml each) were taken into tubes that contained ethylenediaminetetra-acetic acid (EDTA) before drug administration and 0.5, 1, 1.5, 2, 3, 5, 7 and 10 h later. Plasma was separated within 30 min, divided into three tubes and stored at 20 C until analysed. Plasma concentrations of diazepam were determined by gas chromatography using methoxydiazepam as an internal standard [5]. The limit of quantication was 0.5 ng ml1 and the between-day coecients of variation (CV) were 3.2% (mean, 0.97 ng ml1, n=6) and 1 1.9% (mean, 97.8 ng ml , n=6). The concentrations of ibuprofen were measured by high-performance liquid chromatography (h.p.l.c.), using indomethacin as an internal standard [6]. The quantication limit was 0.5 mg l1 and the between-day CVs were 8.0% (mean, 1 1 0.97 mg l , n=12) and 3.4% (mean, 15.5 mg l , n= 12). Plasma concentrations of citalopram were determined by gas chromatography, using amitriptyline as an internal standard [7]. The limit of quantication was 1.0 ng ml1 and the between-day CVs were 5.5% (mean, 2.6 ng ml1, 1 n=6) and 2.2% (mean, 10.4 ng ml , n=5).

Methods Subjects
Nine healthy volunteers (seven women and two men; age range, 1940 years; weight range, 5687 kg) participated in this study. They had no history of gastrointestinal, hepatic or renal disease, and the results of physical examination and routine laboratory tests before the study were normal. None of the subjects used any other medication during the study, except for four women who were using oral contraceptive steroids. These subjects were instructed to take oral contraceptives at least 12 h before or after administration of charcoal. Written informed consent was obtained from each volunteer prior to the study. The study protocol was approved by the Ethics Committee of the Department of Clinical Pharmacology, University of Helsinki and by the Finnish National Agency for Medicines.

Study design
A randomized, balanced, cross-over study design with three phases was used at intervals of 2 weeks. The drugs employed as test drugs and their doses were: 5 mg diazepam (one Stesolid 5 mg tablet, Dumex-Alpharma, Denmark), 400 mg ibuprofen (one Brufen 400 mg tablet, Knoll AG, Germany) and 20 mg citalopram (one Cipramil 20 mg tablet, Lundbeck, Denmark). The drugs were taken simultaneously with 150 ml water at 08.30 h after an overnight fast. Thirty min after taking the drugs the subjects gave a blood sample and were assigned to one of the following treatments: 200 ml water (control), 25 g activated charcoal (Carbomix, Leiras, Finland) as a suspension in 200 ml water or gastric lavage followed by 25 g charcoal in suspension given through the lavage tube. The charcoal suspension was prepared by shaking the charcoal with tap water just before use. Gastric lavage was performed with the subject in the sitting position, using a standard large-bore orogastric tube for lavage. The length of the tube was 80 cm, and the inner diameter was 8 mm and the outer diameter 10 mm. Lavage was performed by two nurses with a long experience in performing gastric lavage of intoxicated patients. For lavage 2 l of warm tap water in repeated 200 ml aliquots was used. Gastric content was aspirated through the lavage tube immediately after each aliquot. A warm standard meal was served 3 h and a snack 7 h after drug administration. All nine volunteers participated in all
1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 148153

Pharmacokinetics
The absorption of diazepam, ibuprofen and citalopram was characterized by the area under the plasma concentration-time curve from 0 to 10 h [AUC(0, 10 h)], calculated with the linear trapezoidal method, the peak plasma concentration (Cmax ) and time to peak (tmax ). A variable CD was calculated to characterize the eect of gastric decontamination procedures ( performed at 0.5 h) on the absorption of the drugs from 0.5 h onwards. The CD was the Cmax minus C0.5 h. However, if the Cmax occurred already at 0.5 h during the charcoal or lavage combined with charcoal phases, the CD was the Cmax minus the concentration measured at the tmax of the control phase.

Statistical analysis
Results are expressed as mean valuess.d. or, in case of tmax, as median with range. 95% condence intervals (CI) were calculated for selected variables. One-way analysis of variance (anova), with the Tukey test used for post hoc comparisons, was used for statistical analysis of the results, except for tmax data which were analysed by the Wilcoxon test. The power of the study to detect a 30%
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Plasma diazepam (ngml1)

dierence in AUC(0,10 h) between two treatments was about 80% at the 5% level of signicance. The level of statistical signicance was P<0.05.

150 125 100 75 50 25 0 0 0.5 1 1.5 2 3 5 Time (h) 7 10

Intervention

Results Diazepam
Both activated charcoal alone and charcoal combined with gastric lavage reduced the AUC(0,10 h) of diazepam by 27% ( P<0.05) (Table 1, Figure 1). The increase in plasma diazepam concentration from 0.5 h onwards (CD ) was prevented both by activated charcoal alone ( P= 0.05) and by gastric lavage combined with charcoal ( P<0.05) (Figure 1 and 4). Neither the Cmax nor the tmax of diazepam was changed signicantly by activated charcoal alone or by charcoal combined with lavage.

Ibuprofen
The AUC(0,10 h) of ibuprofen was reduced by 49% ( P<0.05) when ingestion of charcoal was preceded by gastric lavage and by 30% ( P<0.05) with charcoal alone (Table 1, Figure 2), the dierence between these two treatments being not statistically signicant ( P=0.20). Charcoal alone ( P<0.01) and charcoal given after gastric lavage ( P<0.01) were equally eective in preventing the increase in plasma ibuprofen concentration from 0.5 h onwards (Figure 2 and 4). The Cmax of ibuprofen was reduced by 21% ( P=NS) by charcoal alone and by 45%

Figure 1 Mean plasma concentrations of diazepam in nine healthy volunteers after a 5 mg oral dose, following water (control; &), 25 g activated charcoal ($) or gastric lavage followed by 25 g activated charcoal (+). For clarity, only mean values are given.

( P<0.05) by the combination treatment, with no signicant dierence between the treatments. The tmax occurred earlier (0.5 vs 1.5 h, P<0.05) in the charcoal phase than in the control phase.

Citalopram
The AUC(0,10 h) of citalopram was reduced by 51% ( P<0.05) by both charcoal alone and charcoal preceded

Table 1 Eect of activated charcoal (25 g) and gastric lavage in combination with charcoal (25 g ) on the absorption of diazepam, ibuprofen and citalopram.
AUC(0,10 h) Mean dierence (95% Cl ) between the treatments Cmax # % of control tmax (h)

Diazepam 5 mg +water (control) +activated charcoal at 30 min +lavage and charcoal at 30 min Ibuprofen 400 mg +water (control) +activated charcoal at 30 min +lavage and charcoal at 30 min Citalopram 20 mg +water (control) +activated charcoal at 30 min +lavage and charcoal at 30 min

% of control

69380.9 503160* 508205*

100 73 73

4.9 (167, 157)

15326.1 12647.9 11862.7

100 82 77

1 (0.51.5) 0.5 (0.51) 0.5 (0.51)

11938.3 82.730.1* 60.629.9*

100 70 51

22.1 (14.5, 58.7)

34.76.4 27.310.9 19.111.8*

100 79 55

1.5 (0.53) 0.5 (0.51)* 1 (0.52)

13132.9 63.642.6* 64.140.1*

100 49 49

0.48 (31.8, 30.8)

17.94.9 8.65.9* 8.35.1*

100 48 46

10 (210) 5 (1.510)* 5 (27)*

Data are mean valuess.d. for nine subjects; tmax is given as median (range). *Signicantly ( P<0.05) dierent from control. Unit is ng ml1 h in the case of diazepam and citalopram and mg ml1 h in the case of 1 1 ibuprofen. #Unit is ng ml in the case of diazepam and citalopram and mg ml in the case of ibuprofen.

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Effect of gastric decontamination on absorption of diazepam, ibuprofen and citalopram

Plasma ibuprofen (g ml1)

25 20 15 10 5 0
Intervention

Diazepam CD (ng ml1)

30

40 30 20 10 0 10 20 30

Charcoal Control

Lavage + charcoal

Ibuprofen CD (g ml1)

0 0.5 1 1.5 2

5 Time (h)

10

25 20 15 10 5 0 5 Control Lavage + charcoal Charcoal

Figure 2 Mean plasma concentrations of ibuprofen in nine healthy volunteers after a 400 mg oral dose, following water (control; &), 25 g activated charcoal ($) or gastric lavage followed by 25 g activated charcoal (+). For clarity, only mean values are given.

Citalopram CD (ng ml1)

by gastric lavage (Table 1, Figure 3). These treatments reduced the Cmax of citalopram by 52% ( P<0.05) and 54% ( P<0.05), respectively. Also the CD of citalopram was reduced to the same extent, by about 50%, by both interventions ( P<0.01; Figure 4). The tmax of citalopram occurred earlier (5 vs 10 h, P<0.05) in both gastric decontamination phases than in the control phase.

25 20 15 10 5 0 5 Control Charcoal Lavage + charcoal

Discussion
In intoxicated patients, the considerable heterogeneity of poisonings makes comparison of dierent treatments dicult. Many patients who present to hospital because of intoxication are otherwise healthy and resemble
20
Plasma citalopram (ngml1)

Figure 4 Eect of activated charcoal alone and charcoal in combination with gastric lavage on the absorption of the study drugs from 0.5 h onwards, as measured by CD (means.e.mean, see Methods). *Signicantly dierent from control.

15

0 0 0.5 1 1.5 2 3 5 Time (h) 7 10

Figure 3 Mean plasma concentrations of citalopram in nine healthy volunteers after a 20 mg oral dose, following water (control; &), 25 g activated charcoal ($) or gastric lavage followed by 25 g activated charcoal (+). For clarity, only mean values are given.

Intervention

10

subjects used in volunteer studies. In this study, we used healthy volunteers in order to standardize variables such as drug dose, concomitant medications, delay in presentation and stomach content. We found that the further absorption of diazepam and ibuprofen was prevented or greatly reduced when gastric decontamination by activated charcoal alone or combined with gastric lavage was performed 30 min after drug ingestion, whereas the plasma concentrations of citalopram continued to increase for several hours despite these interventions. The eect of gastric lavage combined with administration of activated charcoal on the absorption of these three test drugs was similar to that of charcoal alone, as shown, e.g. by the 95% CIs for the mean dierence in AUC(0,10 h) between the treatments. Nevertheless, with ibuprofen there was a nonsignicant trend towards a greater
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reduction in the AUC(0,10 h) when lavage was performed before administration of charcoal. In the gastric decontamination phases, the plasma concentrations of diazepam and ibuprofen at 30 min, just before initiating gastric decontamination, were about 5075% of the mean Cmax in the control phase, indicating that most of the drug had already been absorbed by that time. The greatly reduced or even negative CD indicates a good ecacy of charcoal, given either alone or after gastric lavage, in preventing the further absorption of both diazepam and ibuprofen from 0.5 h onwards. In contrast, citalopram was slowly absorbed, and the mean plasma citalopram concentration just before gastric decontamination was less than 5% of the mean Cmax in the control phase. While the modest eect of gastric decontamination on the AUC(0,10 h) of diazepam and ibuprofen is explained by their rapid absorption, the absorption of citalopram was reduced only by about 50%, even though its absorption had barely begun when the treatments were initiated. In the present study, all three drugs were ingested at the same time on an empty stomach in order to ensure comparable absorption conditions for individual drugs. The timing of the gastric decontamination procedures (at 30 min after drug ingestion) was designed to simulate conditions in patients presenting soon after an overdose. Although poisoned patients often present several hours after ingestion of the toxic agent, there are also cases of overdose in which the patient presents without delay [8, 9]. The dose of charcoal used, 25 g, is half the normal single dose used in the treatment of acute poisonings, and it is unlikely that a larger dose would have had a greater eect in the present study in which therapeutic doses of the drugs were ingested. In previous volunteer studies [10], a single dose of activated charcoal given 30 min after ingestion of the test drug reduced absorption on average by about 50%, whereas charcoal given within 5 min of drug ingestion reduced the absorption of most drugs by more than 90%. For example, activated charcoal (50 g) given 30 min after drug ingestion reduced the absorption of paracetamol, tetracycline and slow-release aminophylline by about 40%, 60% and 75%, respectively [11]. As in the present study, these dierences in the ecacy of charcoal seem to reect the dierence in the rates of absorption of these drugs. When the same dose of charcoal was given within 5 min of drug ingestion, the absorption of paracetamol, tetracycline and aminophylline was, however, reduced by about 90%. It is likely that charcoal would also have prevented the absorption of diazepam, ibuprofen and citalopram almost completely if it had been given within a few minutes of ingestion of these drugs. In the few clinical studies that have been performed to compare activated charcoal and charcoal in combination
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with gastric lavage, the clinical outcome was generally similar [3, 4, 12]. For example, Bosse et al. [12] conducted a prospective study of 51 patients presenting with tricyclic antidepressant overdose. The patients were assigned to one of the three treatments: activated charcoal 50 g, gastric lavage followed by charcoal 50 g or charcoal 25 g followed by lavage and charcoal 25 g. There were no signicant dierences in the clinical outcome between the three methods. In fact, there is now a consensus that gastric lavage should not be employed routinely in the management of poisoned patients [2]. However, early lavage may be benecial in some selected patients who have taken a potentially life-threatening amount of a poison, particularly if the agent is not adsorbable by charcoal. Obviously, performing gastric lavage delays the use of activated charcoal [3]. It should also be noted that the eectiveness of all gastrointestinal decontamination procedures, including charcoal, diminishes with time. In the present study, gastric lavage combined with activated charcoal and charcoal alone showed similar eectiveness in preventing the absorption of the test drugs diazepam, ibuprofen and citalopram, although there were large between-subject dierences in the ecacy of both decontamination methods. Notably, no increase in mean plasma drug concentration was seen after gastric lavage. Thus, charcoal given immediately after the gastric lavage was able to bind any drug possibly forced beyond the pylorus by gastric lavage [13]. Extrapolation of the results of the present volunteer study to patients with overdose should be done with some caution. The drug doses tested were, of necessity, therapeutic, resulting in very high charcoal-drug ratios (62.551 for ibuprofen and >100051 for diazepam and citalopram). However, even at a ratio of 1051, 90100% of most drugs is adsorbed onto charcoal in vitro [14], suggesting that the adsorption capacity of the normal single dose (50 g ) of activated charcoal would not be saturated even with a considerably higher dose of diazepam or citalopram than ingested in the present study. By contrast, the adsorption capacity of charcoal may become saturated in large ibuprofen overdoses, impairing the ecacy of charcoal. In addition, drug absorption may be slower after an overdose than after a therapeutic dose; if this were the case, the eectiveness of gastric decontamination procedures would probably not diminish with time as rapidly as after a therapeutic dose. Nevertheless, our ndings give support to the prevailing view that gastric lavage need not be routinely performed before administration of charcoal.

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2 American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists. Position statement: gastric lavage. Clin Toxicol 1997; 35: 711719. 3 Pond SM, Lewis-Driver DJ, Williams GM, Green AC, Stevenson NW. Gastric emptying in acute overdose: a prospective randomised controlled trial. Med J Aust 1995; 163: 345349. 4 Kulig K, Bar-Or D, Cantrill SV, Rosen P, Rumack BH. Management of acutely poisoned patients without gastric emptying. Ann Emerg Med 1985; 14: 562567. 5 Gaillard Y, Gay-Montchamp J-P, Ollagnier M. Simultaneous screening and quantitation of alpidem, zolpidem, buspirone and benzodiazepines by dual-channel gas chromatography using electron-capture and nitrogen-phosphorus detection after solid-phase extraction. J Chromatogr 1993; 622: 197208. 6 Sochor J, Klimes J, Sedlacek J, Zahradnicek M. Determination of ibuprofen in erythrocytes and plasma by high performance liquid chromatography. J Pharm Biomed Anal 1995; 13: 899903. 7 Reymond P, Amey M, Souche A, et al. Determination of plasma levels of citalopram and its demethylated and deaminated metabolites by gas chromatography and gas chromatography-mass spectrometry. J Chromatogr 1993; 616: 221228.

8 Thomas SHL, Bevan L, Bhattacharyya S, et al. Presentation of poisoned patients to accident and emergency departments in the North of England. Hum Exp Toxicol 1996; 15: 466470. 9 Lapatto-Reiniluoto O, Kivisto KT, Pohjola-Sintonen S, Luomanmaki K, Neuvonen PJ. A prospective study of acute poisonings in Finnish hospital patients. Hum Exp Toxicol 1998; 17: 307311. 10 American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists. Position statement: single-dose activated charcoal. Clin Toxicol 1997; 35: 721741. 11 Neuvonen PJ, Vartiainen M, Tokola O. Comparison of activated charcoal and ipecac syrup in prevention of drug absorption. Eur J Clin Pharmacol 1983; 24: 557562. 12 Bosse GM, Barefoot JA, Pfeifer MP, Rodgers GC. Comparison of three methods of gut decontamination in tricyclic antidepressant overdose. J Emerg Med 1995; 13: 203209. 13 Saetta JP, March S, Gaunt ME, Quinton DN. Gastric emptying procedures in the self-poisoned patient: are we forcing gastric content beyond the pylorus? J R Soc Med 1991; 84: 274276. 14 Neuvonen PJ, Olkkola KT. Oral activated charcoal in the treatment of intoxications. Role of single and repeated doses. Med Toxicol 1988; 3: 3358.

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