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Acceleration of Body Clearance of DiethylCarbamazine By Oral Activated Charcoal
Pharmacological Research, Vol. 42, No. 2, 2000 doi: 10.1006/phrs.2000.0667, available online at http://www.idealibrary.com on
ACCELERATION OF BODY CLEARANCE OF DIETHYLCARBAMAZINE BY ORAL ACTIVATED CHARCOAL ORISH E. ORISAKWEa,∗ , NDIDI A. ILONDUa , O. JOHNSON AFONNEa , SABINUS I. OFOEFULEb and CHINNA N. ORISHc a Toxicology
Unit, Department of Pharmacology, College of Health Sciences, Nnamdi Azikiwe University, Nnewi Campus, Anambra State, Nigeria, b Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Nigeria, Nsukka, Enugu State, Nigeria, c Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State, Nigeria Accepted 25 January 2000
The effect of activated charcoal (AC) on body clearance of diethylcarbamazine (DEC) was investigated in six healthy volunteers. On three occasions at weekly intervals, each subject received 150 mg of DEC with 350 ml of water. One and two weeks later, 150 mg of DEC plus 7.5 g and 15 g of AC, respectively, in 350 ml of water as a charcoal slurry. The non-renal clearance of DEC expressed as the total body clearance of DEC was increased after treatment with AC. The 45.2, 79.6 percent and 58.6, 81.6 percent reductions in maximum concentration and area under the concentration–time curve, respectively, suggest an appreciable adsorption of DEC by AC (7.5 and 15 g) in the gut. Serum eliminating half-life was decreased upon treatment with AC (7.5 and 15 g). These results indicate that AC accelerates the body clearance of DEC by increasing non-renal c 2000 Academic Press elimination of the drug.
K EY WORDS : diethylcarbamazine, total body clearance, activated charcoal, maximum concentration.
INTRODUCTION Diethylcarbamazine (N , N -diethyl-4-methyl-l-piperazine carboxamide dihydrogen citrate) (DEC) is a piperazine derivative that is active against filarial infection caused by Wuchereria bancrofti and Loa loa. Toxocarcal caus ocular involvement (enophthalmitis) was treated with DEC in a dose of 3 mg kg−1 , three times daily for 21 days, while patients with eosinophilic meningitis due to T. caus were been treated with 8 mg kg−1 daily for 10 days. In the treatment of W. bancrofti, Brugia timori, Brugia malayi and L. loa, a dose of 6 mg kg−1 daily, in three divided doses for 3 weeks, or 2 mg kg−1 , three times daily, for 21 days, was used. Several million doses of the drug have been administered to people. In most patients with onchocerciasis, the microfilaricidal activity of DEC leads to a series of events having dermal, ocular and systemic components known as mazottic reactions within minutes to hours after treatment. Clinical manifestations may be severe, dangerous, fatal and debilitating, and have limited the widespread use of DEC in onchocerciasis [1, 2]. ∗ Corresponding author. Dr O. E. Orisakwe Toxicology Unit, Depart-
ment of Pharmacology, College of Health Sciences, Nnamdi Azikiwe University, Nnewi Campus, P.M.B. 5001, Nnewi, Anambra State, Nigeria. E-mail: [email protected] 1043–6618/00/020167–04/$35.00/0
Absorption of potentially toxic substances can be inhibited by the removal of the substance from the stomach through emesis or gastric lavage and/or by sequestration of the substance in the gastrointestinal tract with activated charcoal (AC) [3, 4]. The ability of AC to adsorb drugs and other toxins has made administration of AC one of the most effective methods of treating poisonings. In fact, to our knowledge, we are not aware of any previous study on the effects of AC on DEC absorption in man. The purpose of the investigation was to study the effect of AC on the pharmacokinetics of DEC after oral administration.
SUBJECTS AND METHODS Six healthy adult male volunteers, aged 20–27 years (undergraduate and postgraduate students of College of Health Sciences, Nnamdi Azikiwe University, Nnewi Campus, Anambra state, Nigeria) who were normal according to a medical history and physical examination, participated in this three-phased, randomized, cross-over study, after giving informed consent. Subjects were not on any other form of medication. After an overnight fast, c 2000 Academic Press
168
they swallowed 150 mg DEC with 350 ml of water alone (phase I), 150 mg DEC with 7.5 g AC suspended in water at the same time (phase II) and 150 mg DEC with 15 g AC suspended in water simultaneously (phase III). At least a 1-week wash-out period separated the different phases. Serum and urine samples were taken at: 0, 1, 2, 4, 8, 12, and 24 h after the DEC administration.
Pharmacological Research, Vol. 42, No. 2, 2000
the concentration maximum (Cmax ) and corresponding time (Tmax ) were read off from the serum concentration vs time curve. The mean absorption time (MAT) was calculated from the reciprocal of K a . The amount of DEC excreted or recovered in urine was calculated using the method of Ritschel [9].
STATISTICAL ANALYSIS ASSAY METHODOLOGY Blood samples were collected through an in-dwelling heparinized catheter just before and at approximately 0, 1, 2, 4, 8, 12 and 24 h post-DEC administration. The blood samples were immediately centrifuged at 3000 rpm for 10 min and the plasma collected and stored frozen at −20 ◦ C until analysis. DEC concentrations were determined by the colorimetric method [5]. Plasma samples (0.5 ml) were added to test tubes and shaken vigorously with 2 ml of 30% NaOH and 5 ml of ethylene dichloride (ethane-1, 2-dichloride). The samples were then analysed at 432 nm using a Ciba Corning Colorimeter [6]. The calibration curves were produced using DEC concentrations of 1000, 500, 250, 125, 62.5, 31.25, 15.625, 7.813, 3.906 and 1.952 µg ml−1 .
PHARMACOKINETIC ANALYSIS To analyse the serum DEC concentration–time data, we assumed that DEC kinetics after oral administration could be described by a one-compartment open model with linear kinetics. The concentration–time data for each study period 1–24 h after completion of DEC administration were fitted by a non-linear least squares regression to the following equation, C = C0 . e(−kt) where C is the concentration at time t and C0 concentration when t = 0. The elimination half-life (t 1 e ) was calculated from the elimination rate constant 2 (K ) by the formula 0.693/K . The area under the serum concentration-time curve (AUC) was calculated from 0 to 24 h by the trapezoidal rule and was extrapolated to infinity by adding the DEC concentration at 24 h divided by K [7]. The volume of distribution (Vd ) was calculated for each treatment by dividing the dose of DEC by the initial serum concentration of DEC when t is equal to zero. The total body clearance (Cl) with or without the administration of AC was obtained by multiplying Vd by the quantity 0.693 divided by the serum half-life [7, 8]. Renal clearance (Clr) of DEC was calculated by dividing the amount of DEC recovered in urine by the AUC for serum concentrations vs time from 12 to 24 h. The percentage of non-renal clearance (Clnr) for each treatment was obtained by subtracting the Clr from the Cl, multiplying the quantity by 100, then dividing it by the Cl. The method of residuals was used to determine the absorption rate constant (K a ), while
The differences between two related samples were analysed using Student’s t-test (paired). Differences were considered statistically significant at P < 0.05 (two tailed). Data are expressed as mean ± SEM.
RESULTS The mean pharmacokinetic parameters, namely total body clearance (Cl), renal clearance (Clr), percentage non-renal clearance (%Clnr), concentration maximum (Cmax ) and time required to reach concentration maximum (Tmax ), area under the curve at 24 h (AUC0−24 ), area under the curve at infinity (AUC0−∞ ), volume of distribution (Vd ), elimination rate constant (K ), absorption rate constant (K a ), elimination half-life (t 1 e ), absorption half-life (t 1 a ), and mean absorption 2 2 time (MAT) are shown in Table I. Treatment with AC (7.5 and 15 g) significantly (P < 0.05) decreased the serum t 1 e , and increased the Cl and the Vd as compared 2 with treatment without AC. The Clnr of DEC, expressed as a percentage of the Cl of DEC was increased by treatment with AC. Figure 1 shows the concentration of DEC in serum plotted against the length of time after the administration of DEC. Treatment with AC appreciably decreased the AUC and Cmax without altering the Tmax .
DISCUSSION This is apparently the first report on the effect of AC on the pharmacokinetics profile of DEC after oral administration in man. In our subjects, oral administration of AC substantially increased the Cl of DEC and decreased its t 1 e . The validity of these results is supported by the 2 randomized study design and the fact that DEC does not alter its own metabolism. Metabolism is both rapid and extensive [10]. Excretion is by both urinary and extraurinary routes; over 50% of an oral dose appears in acidic urine as the unchanged drug [11]. Methods of enhancing the excretion of DEC such as acidifying urine presumably work by increasing urinary excretion of the unchanged drug. In our study, oral administration of AC increased Clnr of DEC. We conclude that administration of AC increases the Cl of DEC by increasing non-renal elimination of the drug.
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Table I Diethylcarbamazine pharmacokinetic parameters with or without activated charcoal Parameter
Control
DEC + 7.5 g AC
DEC + 15 g AC
Significance
Cmax Tmax (h) K t 1 e (h)
49.00 ± 8.17 2.0 0.08 ± 0.01 8.56 ± 0.32
26.83 ± 0.58 2.0 0.19 ± 0.03 4.73 ± 0.67
13.50 ± 0.58 2.0 0.23 ± 0.02 2.98 ± 0.14
P < 0.05 N.S. P < 0.05 P < 0.05
Ka t 1 a (h)
0.21 ± 0.01 3.43 ± 0.21
0.12 ± 0.01 5.96 ± 1.16
0.09 ± 0.07 7.17 ± 1.52
P < 0.05 P < 0.05
1.37 ± 0.05 195.58 ± 3.68 201.87 ± 4.21 0.86 37.22 7.31 ± 0.78 8.33
1.58 ± 0.09 88.63 ± 4.27 89.94 ± 4.27 1.02 50.96 6.56 ± 0.24 11.11
(µg ml−1 )
2
2
Cl (ml kg−1 h −1 ) AUC0–24 (µg h−1 ml−1 ) AUC0−∝ (µg h−1 ml−1 ) Clr %Clnr Vd MAT
0.71 ± 0.12 428.64 ± 9.17 487.98 ± 12.35 0.71 1.41 8.80 ± 0.23 4.79
P P P P P P P
< 0.05 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05
For all the parameters, n = 6. Values are expressed as mean ± SEM. Abbreviations: n = number of subjects; Cmax , maximum concentration; Tmax , time for maximum concentration; K , elimination rate constant; t 1 e , elimination half-life; K a , absorption rate constant; t 1 a , absorption half-life; Cl, 2
clearance; AUC, area under the concentration-time curve; Vd , volume of distribution; MAT, mean absorption time.
2
4
Fig. 1.
Serum diethylcarbamazine level.
The mechanism of this effect may involve the adsorption of DEC by charcoal in the gastrointestinal tract (GIT), with subsequent excretion in to the stool. Since there is no appreciable enterohepatic circulation of DEC, it is probable that AC, by adsorbing DEC in the gastrointestinal fluids, sets up a concentration gradient between the blood and the fluids in the bowel. Driven by these concentration gradients, DEC diffuses from the blood into the fluids in the bowel and is subsequently adsorbed by the charcoal. Other mechanisms such as trapping of DEC in the GIT, with subsequent adsorption by AC, are unlikely to explain these striking effects of oral charcoal on DEC clearance. These results have some important clinical implications. First of all, the effect of AC is similar in patients with a higher serum concentration of DEC; this treatment may be effective in cases of overdose
as was found in other drugs such as phenobarbital, digoxin, phenylbutazone, theophylline, carbamazepine and methotrexate [12–16]. This study shows conclusively that significant and consistent adsorption of DEC by AC takes place in the gastrointestinal tract of man. Furthermore, the DEC is not released from this complex to a clinically significant extent since serum DEC concentrations continued to decrease in subjects receiving AC. The Cmax is an indicator of the initial impact of a drug exposure and is often used to determine the severity of a poisoning exposure while AUC reflects the total extent of adsorption of the drug. The 45.2, 79.6 and 58.6, 81.6 percent reductions in Cmax and AUC, respectively, suggest an appreciable adsorption of DEC by AC (7.5 and 15 g) in the gut. As a consequence of these findings, the use of AC as a therapeutic agent in the early management of acute DEC ingestion is recommended.
170
REFERENCES 1. Oomen AP. Studies on onchocerciasis and elephantiasis in Ethiopia. Trans R Soc Trop Med Hyg 1969; 63: 548. 2. WHO. WHO Expert Committee on Onchocerciasis. Third Report, 752. 3. Boxer L, Anderson FP, Rowe DS. Comparison of ipecac-induced emesis with gastric lavage in the treatment of acute salicylate ingestion. J Pediatr 1969; 74: 800–3. 4. Decker WJ, Shpall RA, Corby DG, Combs HF, Payne CE. Inhibition of aspirin absorption by activated charcoal and apomorphine. Clin Pharmacol Ther 1969; 4: 710–3. 5. Rao KN, Subrahmanyam D. Estimation of diethylcarbamazine. Indian J Med Res 1970; 58: 746–52. 6. Ramachandran M. Colorimetric determination of diethylcarbamazine with picric acid. Curr Sci 1972; 41: 890. 7. Wagner JG. Fundamentals of clinical pharmacokinetics. Hamilton: Drug Intelligence Publications III, 1975: 63. 8. Gibaldi M, Perrie D. Pharmacokinetics. New York: Marcel Decker, 1975. 9. Ritschel WA. Handbook of basic pharmacokinetics, 2nd edn.
Pharmacological Research, Vol. 42, No. 2, 2000 Illinois: Hamilton Press, 1980: 166. 10. Faulkner JK, Smith KJ. Dealkylation and N-oxidation in the metabolism of 1-diethyl-carbamyl-4-methylpiperazine in the rat. Xenobiotica 1972; 2: 59–68. 11. Edwards G, Breckenride AM, Adjepon Yamaah KK, Orme ML, d Ward SA. The effect of variation in urinary pH on pharmacokinetics of DEC. Br J Clin Pharmacol 1981; 12: 807–12. 12. Neuvonen PJ, Elonen E. Effect of activated charcoal on absorption and elimination of phenobarbitone, carbamazepine and phenylbutazone in man. Eur J Clin Pharmacol 1980; 17: 51–7. 13. Pond S, Jacob M, Marks J, Garner J, Goldschlanger N, Hanser D. Treatment of digitoxin overdose with oral activated charcoal. Lancet 1981; ii: 1177–8. 14. Gadgil SD, Danle SR, Advani SH, Vaidya AB. Effect of activated charcoal on the pharmacokinetics of high dose methotrexate. Cancer Treat Rep 1982; 66: 1169–71. 15. Berg MJ, Berlinger WG, Goldberg MJ, Spector R, Johnson GF. Acceleration of the body clearance of phenobarbital by oral activated charcoal. N Engl J Med 1982; 307: 642–4. 16. Goldberg MJ, Berlinger WG. Treatment of phenobarbital overdose with activated charcoal. JAMA 1982; 247: 2400–1.
ACCELERATION OF BODY CLEARANCE OF DIETHYLCARBAMAZINE BY ORAL ACTIVATED CHARCOAL ORISH E. ORISAKWEa,∗ , NDIDI A. ILONDUa , O. JOHNSON AFONNEa , SABINUS I. OFOEFULEb and CHINNA N. ORISHc a Toxicology
Unit, Department of Pharmacology, College of Health Sciences, Nnamdi Azikiwe University, Nnewi Campus, Anambra State, Nigeria, b Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Nigeria, Nsukka, Enugu State, Nigeria, c Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State, Nigeria Accepted 25 January 2000
The effect of activated charcoal (AC) on body clearance of diethylcarbamazine (DEC) was investigated in six healthy volunteers. On three occasions at weekly intervals, each subject received 150 mg of DEC with 350 ml of water. One and two weeks later, 150 mg of DEC plus 7.5 g and 15 g of AC, respectively, in 350 ml of water as a charcoal slurry. The non-renal clearance of DEC expressed as the total body clearance of DEC was increased after treatment with AC. The 45.2, 79.6 percent and 58.6, 81.6 percent reductions in maximum concentration and area under the concentration–time curve, respectively, suggest an appreciable adsorption of DEC by AC (7.5 and 15 g) in the gut. Serum eliminating half-life was decreased upon treatment with AC (7.5 and 15 g). These results indicate that AC accelerates the body clearance of DEC by increasing non-renal c 2000 Academic Press elimination of the drug.
K EY WORDS : diethylcarbamazine, total body clearance, activated charcoal, maximum concentration.
INTRODUCTION Diethylcarbamazine (N , N -diethyl-4-methyl-l-piperazine carboxamide dihydrogen citrate) (DEC) is a piperazine derivative that is active against filarial infection caused by Wuchereria bancrofti and Loa loa. Toxocarcal caus ocular involvement (enophthalmitis) was treated with DEC in a dose of 3 mg kg−1 , three times daily for 21 days, while patients with eosinophilic meningitis due to T. caus were been treated with 8 mg kg−1 daily for 10 days. In the treatment of W. bancrofti, Brugia timori, Brugia malayi and L. loa, a dose of 6 mg kg−1 daily, in three divided doses for 3 weeks, or 2 mg kg−1 , three times daily, for 21 days, was used. Several million doses of the drug have been administered to people. In most patients with onchocerciasis, the microfilaricidal activity of DEC leads to a series of events having dermal, ocular and systemic components known as mazottic reactions within minutes to hours after treatment. Clinical manifestations may be severe, dangerous, fatal and debilitating, and have limited the widespread use of DEC in onchocerciasis [1, 2]. ∗ Corresponding author. Dr O. E. Orisakwe Toxicology Unit, Depart-
ment of Pharmacology, College of Health Sciences, Nnamdi Azikiwe University, Nnewi Campus, P.M.B. 5001, Nnewi, Anambra State, Nigeria. E-mail: [email protected] 1043–6618/00/020167–04/$35.00/0
Absorption of potentially toxic substances can be inhibited by the removal of the substance from the stomach through emesis or gastric lavage and/or by sequestration of the substance in the gastrointestinal tract with activated charcoal (AC) [3, 4]. The ability of AC to adsorb drugs and other toxins has made administration of AC one of the most effective methods of treating poisonings. In fact, to our knowledge, we are not aware of any previous study on the effects of AC on DEC absorption in man. The purpose of the investigation was to study the effect of AC on the pharmacokinetics of DEC after oral administration.
SUBJECTS AND METHODS Six healthy adult male volunteers, aged 20–27 years (undergraduate and postgraduate students of College of Health Sciences, Nnamdi Azikiwe University, Nnewi Campus, Anambra state, Nigeria) who were normal according to a medical history and physical examination, participated in this three-phased, randomized, cross-over study, after giving informed consent. Subjects were not on any other form of medication. After an overnight fast, c 2000 Academic Press
168
they swallowed 150 mg DEC with 350 ml of water alone (phase I), 150 mg DEC with 7.5 g AC suspended in water at the same time (phase II) and 150 mg DEC with 15 g AC suspended in water simultaneously (phase III). At least a 1-week wash-out period separated the different phases. Serum and urine samples were taken at: 0, 1, 2, 4, 8, 12, and 24 h after the DEC administration.
Pharmacological Research, Vol. 42, No. 2, 2000
the concentration maximum (Cmax ) and corresponding time (Tmax ) were read off from the serum concentration vs time curve. The mean absorption time (MAT) was calculated from the reciprocal of K a . The amount of DEC excreted or recovered in urine was calculated using the method of Ritschel [9].
STATISTICAL ANALYSIS ASSAY METHODOLOGY Blood samples were collected through an in-dwelling heparinized catheter just before and at approximately 0, 1, 2, 4, 8, 12 and 24 h post-DEC administration. The blood samples were immediately centrifuged at 3000 rpm for 10 min and the plasma collected and stored frozen at −20 ◦ C until analysis. DEC concentrations were determined by the colorimetric method [5]. Plasma samples (0.5 ml) were added to test tubes and shaken vigorously with 2 ml of 30% NaOH and 5 ml of ethylene dichloride (ethane-1, 2-dichloride). The samples were then analysed at 432 nm using a Ciba Corning Colorimeter [6]. The calibration curves were produced using DEC concentrations of 1000, 500, 250, 125, 62.5, 31.25, 15.625, 7.813, 3.906 and 1.952 µg ml−1 .
PHARMACOKINETIC ANALYSIS To analyse the serum DEC concentration–time data, we assumed that DEC kinetics after oral administration could be described by a one-compartment open model with linear kinetics. The concentration–time data for each study period 1–24 h after completion of DEC administration were fitted by a non-linear least squares regression to the following equation, C = C0 . e(−kt) where C is the concentration at time t and C0 concentration when t = 0. The elimination half-life (t 1 e ) was calculated from the elimination rate constant 2 (K ) by the formula 0.693/K . The area under the serum concentration-time curve (AUC) was calculated from 0 to 24 h by the trapezoidal rule and was extrapolated to infinity by adding the DEC concentration at 24 h divided by K [7]. The volume of distribution (Vd ) was calculated for each treatment by dividing the dose of DEC by the initial serum concentration of DEC when t is equal to zero. The total body clearance (Cl) with or without the administration of AC was obtained by multiplying Vd by the quantity 0.693 divided by the serum half-life [7, 8]. Renal clearance (Clr) of DEC was calculated by dividing the amount of DEC recovered in urine by the AUC for serum concentrations vs time from 12 to 24 h. The percentage of non-renal clearance (Clnr) for each treatment was obtained by subtracting the Clr from the Cl, multiplying the quantity by 100, then dividing it by the Cl. The method of residuals was used to determine the absorption rate constant (K a ), while
The differences between two related samples were analysed using Student’s t-test (paired). Differences were considered statistically significant at P < 0.05 (two tailed). Data are expressed as mean ± SEM.
RESULTS The mean pharmacokinetic parameters, namely total body clearance (Cl), renal clearance (Clr), percentage non-renal clearance (%Clnr), concentration maximum (Cmax ) and time required to reach concentration maximum (Tmax ), area under the curve at 24 h (AUC0−24 ), area under the curve at infinity (AUC0−∞ ), volume of distribution (Vd ), elimination rate constant (K ), absorption rate constant (K a ), elimination half-life (t 1 e ), absorption half-life (t 1 a ), and mean absorption 2 2 time (MAT) are shown in Table I. Treatment with AC (7.5 and 15 g) significantly (P < 0.05) decreased the serum t 1 e , and increased the Cl and the Vd as compared 2 with treatment without AC. The Clnr of DEC, expressed as a percentage of the Cl of DEC was increased by treatment with AC. Figure 1 shows the concentration of DEC in serum plotted against the length of time after the administration of DEC. Treatment with AC appreciably decreased the AUC and Cmax without altering the Tmax .
DISCUSSION This is apparently the first report on the effect of AC on the pharmacokinetics profile of DEC after oral administration in man. In our subjects, oral administration of AC substantially increased the Cl of DEC and decreased its t 1 e . The validity of these results is supported by the 2 randomized study design and the fact that DEC does not alter its own metabolism. Metabolism is both rapid and extensive [10]. Excretion is by both urinary and extraurinary routes; over 50% of an oral dose appears in acidic urine as the unchanged drug [11]. Methods of enhancing the excretion of DEC such as acidifying urine presumably work by increasing urinary excretion of the unchanged drug. In our study, oral administration of AC increased Clnr of DEC. We conclude that administration of AC increases the Cl of DEC by increasing non-renal elimination of the drug.
Pharmacological Research, Vol. 42, No. 2, 2000
169
Table I Diethylcarbamazine pharmacokinetic parameters with or without activated charcoal Parameter
Control
DEC + 7.5 g AC
DEC + 15 g AC
Significance
Cmax Tmax (h) K t 1 e (h)
49.00 ± 8.17 2.0 0.08 ± 0.01 8.56 ± 0.32
26.83 ± 0.58 2.0 0.19 ± 0.03 4.73 ± 0.67
13.50 ± 0.58 2.0 0.23 ± 0.02 2.98 ± 0.14
P < 0.05 N.S. P < 0.05 P < 0.05
Ka t 1 a (h)
0.21 ± 0.01 3.43 ± 0.21
0.12 ± 0.01 5.96 ± 1.16
0.09 ± 0.07 7.17 ± 1.52
P < 0.05 P < 0.05
1.37 ± 0.05 195.58 ± 3.68 201.87 ± 4.21 0.86 37.22 7.31 ± 0.78 8.33
1.58 ± 0.09 88.63 ± 4.27 89.94 ± 4.27 1.02 50.96 6.56 ± 0.24 11.11
(µg ml−1 )
2
2
Cl (ml kg−1 h −1 ) AUC0–24 (µg h−1 ml−1 ) AUC0−∝ (µg h−1 ml−1 ) Clr %Clnr Vd MAT
0.71 ± 0.12 428.64 ± 9.17 487.98 ± 12.35 0.71 1.41 8.80 ± 0.23 4.79
P P P P P P P
< 0.05 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05
For all the parameters, n = 6. Values are expressed as mean ± SEM. Abbreviations: n = number of subjects; Cmax , maximum concentration; Tmax , time for maximum concentration; K , elimination rate constant; t 1 e , elimination half-life; K a , absorption rate constant; t 1 a , absorption half-life; Cl, 2
clearance; AUC, area under the concentration-time curve; Vd , volume of distribution; MAT, mean absorption time.
2
4
Fig. 1.
Serum diethylcarbamazine level.
The mechanism of this effect may involve the adsorption of DEC by charcoal in the gastrointestinal tract (GIT), with subsequent excretion in to the stool. Since there is no appreciable enterohepatic circulation of DEC, it is probable that AC, by adsorbing DEC in the gastrointestinal fluids, sets up a concentration gradient between the blood and the fluids in the bowel. Driven by these concentration gradients, DEC diffuses from the blood into the fluids in the bowel and is subsequently adsorbed by the charcoal. Other mechanisms such as trapping of DEC in the GIT, with subsequent adsorption by AC, are unlikely to explain these striking effects of oral charcoal on DEC clearance. These results have some important clinical implications. First of all, the effect of AC is similar in patients with a higher serum concentration of DEC; this treatment may be effective in cases of overdose
as was found in other drugs such as phenobarbital, digoxin, phenylbutazone, theophylline, carbamazepine and methotrexate [12–16]. This study shows conclusively that significant and consistent adsorption of DEC by AC takes place in the gastrointestinal tract of man. Furthermore, the DEC is not released from this complex to a clinically significant extent since serum DEC concentrations continued to decrease in subjects receiving AC. The Cmax is an indicator of the initial impact of a drug exposure and is often used to determine the severity of a poisoning exposure while AUC reflects the total extent of adsorption of the drug. The 45.2, 79.6 and 58.6, 81.6 percent reductions in Cmax and AUC, respectively, suggest an appreciable adsorption of DEC by AC (7.5 and 15 g) in the gut. As a consequence of these findings, the use of AC as a therapeutic agent in the early management of acute DEC ingestion is recommended.
170
REFERENCES 1. Oomen AP. Studies on onchocerciasis and elephantiasis in Ethiopia. Trans R Soc Trop Med Hyg 1969; 63: 548. 2. WHO. WHO Expert Committee on Onchocerciasis. Third Report, 752. 3. Boxer L, Anderson FP, Rowe DS. Comparison of ipecac-induced emesis with gastric lavage in the treatment of acute salicylate ingestion. J Pediatr 1969; 74: 800–3. 4. Decker WJ, Shpall RA, Corby DG, Combs HF, Payne CE. Inhibition of aspirin absorption by activated charcoal and apomorphine. Clin Pharmacol Ther 1969; 4: 710–3. 5. Rao KN, Subrahmanyam D. Estimation of diethylcarbamazine. Indian J Med Res 1970; 58: 746–52. 6. Ramachandran M. Colorimetric determination of diethylcarbamazine with picric acid. Curr Sci 1972; 41: 890. 7. Wagner JG. Fundamentals of clinical pharmacokinetics. Hamilton: Drug Intelligence Publications III, 1975: 63. 8. Gibaldi M, Perrie D. Pharmacokinetics. New York: Marcel Decker, 1975. 9. Ritschel WA. Handbook of basic pharmacokinetics, 2nd edn.
Pharmacological Research, Vol. 42, No. 2, 2000 Illinois: Hamilton Press, 1980: 166. 10. Faulkner JK, Smith KJ. Dealkylation and N-oxidation in the metabolism of 1-diethyl-carbamyl-4-methylpiperazine in the rat. Xenobiotica 1972; 2: 59–68. 11. Edwards G, Breckenride AM, Adjepon Yamaah KK, Orme ML, d Ward SA. The effect of variation in urinary pH on pharmacokinetics of DEC. Br J Clin Pharmacol 1981; 12: 807–12. 12. Neuvonen PJ, Elonen E. Effect of activated charcoal on absorption and elimination of phenobarbitone, carbamazepine and phenylbutazone in man. Eur J Clin Pharmacol 1980; 17: 51–7. 13. Pond S, Jacob M, Marks J, Garner J, Goldschlanger N, Hanser D. Treatment of digitoxin overdose with oral activated charcoal. Lancet 1981; ii: 1177–8. 14. Gadgil SD, Danle SR, Advani SH, Vaidya AB. Effect of activated charcoal on the pharmacokinetics of high dose methotrexate. Cancer Treat Rep 1982; 66: 1169–71. 15. Berg MJ, Berlinger WG, Goldberg MJ, Spector R, Johnson GF. Acceleration of the body clearance of phenobarbital by oral activated charcoal. N Engl J Med 1982; 307: 642–4. 16. Goldberg MJ, Berlinger WG. Treatment of phenobarbital overdose with activated charcoal. JAMA 1982; 247: 2400–1.