pharmacokinetics, urinary excretion and plasma protein binding of 2,3-butanedione monoxime in goats

5
Small Ruminant Research 93 (2010) 19–23 Contents lists available at ScienceDirect Small Ruminant Research journal homepage: www.elsevier.com/locate/smallrumres Pharmacokinetics, urinary excretion and plasma protein binding of 2,3-butanedione monoxime in goats Anu Rahal a,, J.K. Malik b a Department of Pharmacology and Toxicology, College of Veterinary & Animal Sciences, G.B. Pant University of Agriculture & Technology, Pantnagar 263145 (UA), India b Indian Veterinary Research Institute, Izatnagar, Bareilly 243122 (UP), India article info Article history: Received 2 November 2009 Received in revised form 15 April 2010 Accepted 16 April 2010 Available online 21 May 2010 Keywords: 2,3-Butanedione monoxime Goats Pharmacokinetics Blood Plasma Urine abstract Inhibition of acetylcholinesterase in the central and peripheral nervous system is the basic mechanism of action of organophosphate nerve agents. Of the several phospho- rylated acetylcholinesterase reactivators available, 2,3-butanedione monoxime has been reported to successfully reactive acetylcholinesterase enzyme in central nervous system of domestic animals severely poisoned with organophosphorus insecticides. The blood levels of cholinesterase reactivator 2,3-butanedione monoxime (common name diacetyl monoxime; abbreviated as DAM) were determined in goats following single dose intra- venous administration @ 30 mg/kg body weight injected as 6% solution. Blood and urine samples were collected at different predetermined time intervals and DAM was analysed by colorimetric method with the minimum detection of 1.0 g ml 1 . The pharmacokinetic parameters were determined by employing two-compartment open model. The t 1/2 , t 1/2 , Vd area and Cl B were calculated to be 6.02 ± 2.65 min, 103.3 ± 8.54 min, 548.86 ± 96.53 ml/kg and 3.64 ± 0.41 ml/kg/min, respectively. Approximately 10.44% of the total administered dose was eliminated in urine within 24 h. The plasma protein binding was estimated by equilibrium dialysis technique. The in vitro plasma protein binding of DAM was 54.4%. Based on these data, a satisfactory intravenous dosage regimen of DAM in goats would be 28 mg/kg body weight repeated at 6 h intervals. © 2010 Elsevier B.V. All rights reserved. 1. Introduction Organophosphate (OP) poisoning poses a great danger to both military and civilian populations. Their wide- spread use as pesticides and the availability of highly toxic OP-type potential chemical warfare agents (nerve agents) underline the necessity for an effective medical treatment. The OP toxicity is primarily caused by inhibition of acetyl- cholinesterase (AChE, EC 3.1.1.7) and the pharmacological Corresponding author at: Department of Veterinary Pharmacology & Toxicology, College of Veterinary &Animal Sciences, G.B. Pant University of Agriculture & Technology, Pantnagar 263145 (UA), India. Tel.: +91 5944 233069. E-mail address: [email protected] (A. Rahal). treatment of OP poisoning is based on the reactivation of nonaged AchE using oximes as well as anticholinergic and anticonvulsant drugs for symptomatic relief (Bajgar et al., 2008). The important sites of inhibition of AchE are central (frontal cortex, pontomedullar area, nucleus ruber of brain) and peripheral nervous system (synaptic and neuromus- cular junctions). The dosage schedule and levels of an oxime at the target organs and blood have a direct bear- ing on its therapeutic effect. The commonly used oximes are quaternary compounds with questionable capacity to penetrate through the blood–brain barrier. This serves as a major constraint in the treatment of OP poisoning. Diacetyl monoxime is a cholinesterase reactivator which has high penetration into cerebrospinal fluid (Dultz et al., 1957). 0921-4488/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.smallrumres.2010.04.025

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Small Ruminant Research 93 (2010) 19–23

Contents lists available at ScienceDirect

Small Ruminant Research

journa l homepage: www.e lsev ier .com/ locate /smal l rumres

harmacokinetics, urinary excretion and plasma protein binding of,3-butanedione monoxime in goats

nu Rahala,∗, J.K. Malikb

Department of Pharmacology and Toxicology, College of Veterinary & Animal Sciences, G.B. Pant University of Agriculture & Technology, Pantnagar 263145UA), IndiaIndian Veterinary Research Institute, Izatnagar, Bareilly 243122 (UP), India

r t i c l e i n f o

rticle history:eceived 2 November 2009eceived in revised form 15 April 2010ccepted 16 April 2010vailable online 21 May 2010

eywords:,3-Butanedione monoximeoatsharmacokineticsloodlasma

a b s t r a c t

Inhibition of acetylcholinesterase in the central and peripheral nervous system is thebasic mechanism of action of organophosphate nerve agents. Of the several phospho-rylated acetylcholinesterase reactivators available, 2,3-butanedione monoxime has beenreported to successfully reactive acetylcholinesterase enzyme in central nervous systemof domestic animals severely poisoned with organophosphorus insecticides. The bloodlevels of cholinesterase reactivator 2,3-butanedione monoxime (common name diacetylmonoxime; abbreviated as DAM) were determined in goats following single dose intra-venous administration @ 30 mg/kg body weight injected as 6% solution. Blood and urinesamples were collected at different predetermined time intervals and DAM was analysedby colorimetric method with the minimum detection of 1.0 �g ml−1. The pharmacokineticparameters were determined by employing two-compartment open model. The t1/2�, t1/2�,

rine Vdarea and ClB were calculated to be 6.02 ± 2.65 min, 103.3 ± 8.54 min, 548.86 ± 96.53 ml/kgand 3.64 ± 0.41 ml/kg/min, respectively. Approximately 10.44% of the total administereddose was eliminated in urine within 24 h. The plasma protein binding was estimated byequilibrium dialysis technique. The in vitro plasma protein binding of DAM was 54.4%.

Based on these data, a satisfactory intravenous dosage regimen of DAM in goats wouldweight

be 28 mg/kg body

. Introduction

Organophosphate (OP) poisoning poses a great dangero both military and civilian populations. Their wide-pread use as pesticides and the availability of highly toxic

P-type potential chemical warfare agents (nerve agents)nderline the necessity for an effective medical treatment.he OP toxicity is primarily caused by inhibition of acetyl-holinesterase (AChE, EC 3.1.1.7) and the pharmacological

∗ Corresponding author at: Department of Veterinary Pharmacology &oxicology, College of Veterinary &Animal Sciences, G.B. Pant Universityf Agriculture & Technology, Pantnagar 263145 (UA), India.el.: +91 5944 233069.

E-mail address: [email protected] (A. Rahal).

921-4488/$ – see front matter © 2010 Elsevier B.V. All rights reserved.oi:10.1016/j.smallrumres.2010.04.025

repeated at 6 h intervals.© 2010 Elsevier B.V. All rights reserved.

treatment of OP poisoning is based on the reactivation ofnonaged AchE using oximes as well as anticholinergic andanticonvulsant drugs for symptomatic relief (Bajgar et al.,2008).

The important sites of inhibition of AchE are central(frontal cortex, pontomedullar area, nucleus ruber of brain)and peripheral nervous system (synaptic and neuromus-cular junctions). The dosage schedule and levels of anoxime at the target organs and blood have a direct bear-ing on its therapeutic effect. The commonly used oximesare quaternary compounds with questionable capacity to

penetrate through the blood–brain barrier. This servesas a major constraint in the treatment of OP poisoning.Diacetyl monoxime is a cholinesterase reactivator whichhas high penetration into cerebrospinal fluid (Dultz et al.,1957).

uminant Research 93 (2010) 19–23

20 A. Rahal, J.K. Malik / Small R

The earlier pharmacokinetic study of DAM and otherAchE reactivators, conducted in buffalo, sheep, rat and manhave revealed marked species difference. Moreover, theplasma levels and pharmacokinetics of drugs, which pro-vides the basis for the determination of their satisfactorydosage regimen, are relevant only when they are under-taken in the animal species in which the drugs are to beused clinically.

Such information on pharmacokinetics of DAM in goatsis completely lacking. The present investigation was, there-fore, planned to study the pharmacokinetics of DAM ingoats and determine its dosage regimen. In addition, theerythrocytic penetration, urinary excretion as well as invitro plasma protein binding of DAM was also determined.

2. Materials and methods

Six healthy goats (20 ± 2 kg body weight, 2–2.5 years of age) were pro-cured from the local market and maintained in the departmental animalshed for 15 days before the commencement of experiment. During thisperiod, animals were fed green fodder and water ad libitum. The proto-col of the experiment was approved by the Institutional Animal EthicalCommittee of Indian Veterinary Research Institute, Izatnagar.

To study the pharmacokinetics, DAM (obtained from Sisco ResearchLaboratory Pvt., Ltd., Mumbai) was administered as 6% solution asepti-cally in isotonic saline into left external jugular vein of animal in a singlebolus dose of 30 mg/kg body weight. To evaluate the blood, plasma anderthryocytic concentrations of DAM, 5 ml of whole blood samples werewithdrawn from contralateral external jugular vein into heparinized glasstest tubes at 0, 2, 5, 10, 20, 30, 45, 60 and 90 min and 2, 3, 4, 5, 7, 10, 12and 24 h after the drug administration. Immediately after blood collection,packed cell volume (PCV) of the sample was assessed by capillary method.From the total blood sample collected, 1.6 ml of blood was deproteinisedusing 0.4 ml of 50% trichloroacetic acid, centrifuged and supernatant col-lected to determine the concentration in blood and rest of the blood wasused to harvest plasma by centrifugation at room temperature. Plasmawas also deproteinised using 50% trichloroacetic acid (ratio 4:1), cen-trifuged and supernatant collected. All the supernatants were stored at−20 ◦C till analysis, usually next day.

For urinary excretion study, Foley’s pediatric catheter no.14F waspassed into the urinary bladder of the animal and held in position byinflating about 30 ml of air in its balloon prior to drug administration withits external end clamped so that the whole amount of urine formed byanimal can be collected at any predetermined time interval without anycontamination and spillage. Following administration of DAM, urine sam-ples were collected at 0, 1, 2, 3, 6, 12 and 24 h intervals. The total volumeof urine was measured and sample of 10 ml each were stored at −20 ◦Ctill further analysis.

The levels of DAM in deproteinised blood and plasma and urine weremeasured by spectrophotometric method as described by Dultz et al.(1957). 0.9 ml of supernatant was hydrolysed with 0.1 ml of 2N hydrochlo-ric acid in boiling water bath for 1 h. Thereafter it was allowed to cool toroom temperature. Then 1 ml of sulfanilic acid (1%) and 0.5 ml of iodinesolution (1.3%) were added, shaking the tube vigorously after each addi-tion. The excess iodine was reduced after 5 min by adding 1 ml of 1%sodium arsenite. Then, 1 ml of 0.02% N-[naphthyl-(1)]ethylene diammo-nium dichloride (NEDD) was added and the contents mixed thoroughlyand kept at room temperature. After 30 min, the volume in each tube wasmade up to 5 ml with distilled water and absorbance was measured usingspectrometer (Spectrocolorimeter 103) at 550 nm.

The standard curves were prepared in blank blood, plasma and urineby spiking them with known concentrations of the drug and processingthem as described above. The exact concentration of DAM in sample wascalculated with standard curve, simultaneously prepared in blood, plasmaand urine of goats. The erythrocyte penetration of DAM was calculated

using the blood and plasma levels and PCV values. The minimum detec-tion level of DAM by this method was 1.0 �g ml−1. The standard curveof DAM was in straight line between concentrations 1.0–40 �g ml−1 inblood, plasma and urine. The value of regression coefficients of straightlines of standard curve were 0.96. The initial pharmacokinetic parameterswere computed by least square technique as described by the methods of

Fig. 1. Mean ± SE blood, plasma and erythrocyte concentrations (�g ml−1)vs. time plot of 2,3-butanedione monoxime following single dose(30 mg kg−1) i.v. administration in goats (n = 6).

Baggot (1977) and Gibaldi and Perrier (1982). The kinetic analysis wasthen done using a non-linear curve fitting programme (statis version 3,M/s clydesoft, Glasgow, U.K.). The dosage regimen was computed by themethod of Baggot (1977) and JohuDein (1980). The minimum concen-tration required for treatment is ≥4 �g ml−1(Sundwall, 1961) was takenas the desired therapeutic concentration Cp (min). To maintain Cp (min),after selecting the appropriate dosage intervals, the priming (D) and main-tenance (D1) doses have been calculated using the following formulae:

D = Cp (min).Vd (area).eˇ�

D1 = Cp (min).Vd (area)(eˇ� − 1)

In vitro plasma protein binding of DAM was determined by the equi-librium dialysis technique as described by Kunin et al. (1959). Plasma withknown concentration of DAM i.e. 2, 4, 8, 20 and 40 �g ml−1 was dialysed(pore size, 40 Å) with phosphate buffer (0.2 M; pH 7.4) for 24 h at 37 ◦C.

To calculate the fraction of DAM undergoing urinary excretion, thetotal volume of urine voided was multiplied by concentration of sampleand divided by total dose administered. The fraction was multiplied by100 to convert it to percentage urinary excretion.

3. Results and discussion

In the present study, 2,3-butanedione monoxime wasgiven in a dose of 30 mg/kg by intravenous route of admin-istration. The dosage level employed is quite comparableto doses given for treatment of organophosphate poison-ing in man and various animal species (Jager et al., 1958;Wright et al., 1966; Ecobichon, 1976). No information aboutthe therapeutic concentration of DAM has been reported.Therefore, the concentration of ≥4 �g ml−1 reported to bethe therapeutic level for pralidoxime has been taken asthat for DAM. Blood, plasma and erythrocytic levels ofDAM at various time intervals after its single intravenousadministration (30 mg/kg) are given in Table 1 (Fig. 1).At 2 min, the peak plasma level was 86.83 ± 8.00 �g ml−1,which rapidly declined to 60.83 ± 3.44 �g ml−1 at 10 min.The values of pharmacokinetic parameters are presented in

Table 2. Tables 3 and 4 represents the renal excretion andin vitro plasma protein binding of DAM in goats.

Following single i.v. administration, the therapeuticplasma concentration of DAM (>4 �g ml−1) was maintainedfrom 1 to 360 min. A relatively higher peak concen-

A. Rahal, J.K. Malik / Small Ruminant Research 93 (2010) 19–23 21

Table 1Plasma concentrations (�g ml−1) of DAM following single dose (30 mg kg−1) i.v. administration of DAM in goats (mean ± SE; n = 6).

Time (min) Blood (�g ml−1) Plasma (�g ml−1) Erythrocytes (�g ml−1)

2 57.6 ± 5.08 86.83 ± 8.00 6.10 ± 0.965 45.4 ± 3.70 66.67 ± 4.81 10.95 ± 2.11

10 40.8 ± 2.17 60.83 ± 3.44 10.07 ± 1.5720 38.3 ± 1.92 55.83 ± 3.45 9.03 ± 2.6730 34.45 ± 3.08 51.0 ± 5.16 8.17 ± 1.5645 30.1 ± 3.26 44.42 ± 4.96 7.94 ± 1.4060 26.2 ± 3.03 37.17 ± 4.21 7.99 ± 2.5990 20.05 ± 2.07 28.46 ± 3.45 6.44 ± 0.68

120 17.7 ± 2.14 23.38 ± 3.64 7.66 ± 1.95180 13.95 ± 1.74 18.08 ± 2.66 6.92 ± 1.06240 9.7 ± 1.27 12.79 ± 1.72 4.61 ± 1.29300 6.75 ± 0.88360 5.05 ± 0.66420 3.4 ± 0.60480 1.75 ± 0.67

Table 2Pharmacokinetic parameters (mean ± SE) of DAM in plasma following sin-gle dose (30 mg kg−1, i.v.) administration of DAM in goats (n = 6).

Kinetic parameter Unit Mean ± SE

A �g ml−1 10.72 ± 48.16B �g ml−1 58.55 ± 48.14˛ min−1 0.45 ± 0.21ˇ min−1 0.007 ± 0.0005t1/2�/t1/2Ka min 6.02 ± 2.65t1/2� min 103.3 ± 8.54AUC �g min ml−1 8803.3 ± 1034.75AUMC �g min2 ml−1 1124398.0 ± 182881.2MRT min 126.44 ± 12.67Vdarea ml kg−1 548.86 ± 96.53Vc ml kg−1 277.51 ± 71.03Vp ml kg−1 240.0 ± 45.33Vdss ml kg−1 386.0 ± 93.62ClB ml kg−1 min−1 3.64 ± 0.41Fc Ratio 1.18 ± 0.61T/p Ratio 1.38 ± 0.65

A: zero time intercept of distribution slope in the two-compartmentmodel, B: zero time intercept of elimination slope in the two-compartment model, ˛: distribution rate constant, ˇ: elimination rateconstant, t1/2�: distribution half-life, t1/2ˇ: elimination half-life, ClB: clear-ance of drug, Vdarea: apparent volume of distribution, Vc: volume of centralcompartment, Vp: volume of peripheral compartment, Vdss: volume ofdistribution at steady state, AUC: total area under the concentration timecurve, AUMC: total area under the first moment concentration time curve,MRT: mean residence time, Fc: fraction of drug in the central compartmentand T/p: tissue plasma ratio, values are expressed as mean ± SE.

Table 3Urinary excretion of DAM in goats following intravascular administrationof DAM (@ 30 mg/kg).

Hours Per cent excretion Per cent cumulativeexcretion

1 1.03 ± 0.18 1.03 ± 0.182 0.72 ± 0.10 1.75 ± 0.29

tcdaa

3 1.12 ± 0.92 2.86 ± 0.386 2.92 ± 0.35 5.79 ± 0.50

12 2.84 ± 0.78 8.62 ± 0.9924 1.82 ± 0.39 10.44 ± 0.70

ration in plasma has been observed earlier in buffaloalves. The maximal concentration in buffalo calves wasose dependent and therapeutic level was maintained forpproximately double the duration than in goats (Maliknd Srivastava, 1986). Evaluation of the semilogarithmic

8.83 ± 0.95 3.93 ± 1.145.46 ± 0.75 3.93 ± 0.833.25 ± 1.00 2.67 ± 0.351.63 ± 0.70 –

plot of plasma level-time curve revealed distinct distri-bution and elimination phases in two-compartment openmodel and described by biexponential equation:

Cp = Ae−˛t + Be−ˇt

where Cp is the concentration of DAM in plasma at timet, ˛ and ˇ are distribution and elimination rate constants,respectively. A and B are zero time intercepts of initialand terminal phases of plasma concentration time curve,respectively. DAM has also been reported to follow two-compartment open model in rats, buffalo calves, sheep andhuman beings.

The distribution rate constant was high which is inperfect agreement with a very rapid distribution andthe apparent equilibrium between blood and tissues wasmaintained within10 min in comparison to 20 and 40 minreported in rats and dogs, respectively (Jager et al., 1958).The longer values of elimination half-life (103.3 ± 8.54 min)and MRT (126.44 ± 12.67 min) revealed that DAM is slowlyeliminated from the body of goats. The elimination half-life of DAM has been calculated to be 88 min in female ratsand 124 min in male rats (Moorthy et al., 1981). The t1/2� ofpralidoxime in healthy sheep (Srivastava and Malik, 1989)and buffalo calves (Srivastava and Malik, 1988) have beenfound to be 1.99 + 0.15 and 5.25 + 0.05 h, respectively.

The short distribution half-life of DAM indicated thatDAM is rapidly distributed in various body fluids andtissues of bovine species. Further, DAM is more rapidlytransferred from central to peripheral compartment thanreturning back from peripheral to central compartment,the values of K12 and K21 ranging from 0.310 ± 0.172to 0.135 ± 0.039 min−1, respectively. Clinically it is moreimportant to determine the extent of penetration ratherthan the rate of distribution. The calculated high values ofVd (area) and T/p ratio indicated that DAM has extensivepenetration into various body tissues and fluids of goats.This is further substantiated by low values of clearance.Similar to present study high values of Vd (area) and T/p

ratio of pralidoxime have also been reported in sheep andbuffalo calves (Srivastava and Malik, 1988, 1989). The val-ues of Vd (area) and T/p ratio in sheep and buffalo calveswere 1.08 + 0.26 l/kg and 4.39 + 0.98, and 1.01 + 0.05 l/kgand 5.12 + 0.44, respectively.

22 A. Rahal, J.K. Malik / Small Ruminant Research 93 (2010) 19–23

Table 4In vitro binding of DAM to plasma proteins of goats.

Parameters (unit) Concentration Mean ± SE

Plasma protein binding(per cent)

2 54.51 ± 0.844 59.40 ± 0.588 55.60 ± 1.41

20 51.75 ± 1.4340 50.7 ± 0.88

Ii (per cent) 2 101.63 ± 0.814 84.54 ± 1.888 96.41 ± 5.26

20 110.13 ± 5.3940 114.19 ± 3.19

mi (mole g−1) 25.9 × 10−9 ± 4.47 × 10−9

Bi (mole g−1) 5.98 × 10−8 ± 1.03 × 10−8

k� 10.27 × 10−6 ± 7.52 × 10−6

mi: slope of line, Bi: drug binding capacity and k�: dissociation constant.

Table 5Intravenous priming (D′) and maintenance (Dm) doses of DAM calculated on the basis of pharmacokinetic parameters at various dosage intervals.

Dosinginterval (h)

Priming dose (D′)(mg/kg)

Maximum plasmaconcentration afterD′ (Cpmax)

−1

Minimum plasmaconcentration afterD′ (Cpmin)

−1)

Maintenance dose(Dm) (mg/kg)

Maximum plasmaconcentration afterDm (Cpmax)

−1

Minimum plasmaconcentration afterDm (Cpmin)

−1

(�g ml ) (�g ml

4 11.8 26.4 4.95 18.0 37.2 4.66 28.0 54.0 4.4

The effectiveness of acetylcholinesterase reactivators isalso certainly dependent on their plasma protein bindingand penetration into erythrocytes, as organophosphorusinsecticides are well known to inhibit the erythrocyte ChEto greater extent than other esterases (Srivastava et al.,1984). Accordingly, it was also thought important to cal-culate the extent of penetration of DAM into erythrocytes.At different blood concentrations, DAM penetrates intoerythrocytes to the extent of 10.6–78.5% of total blood con-centration. Any correlation between concentration of DAMin blood and extent of penetration into erythrocytes couldnot be established. Good penetration of DAM into erythro-cytes reflects that DAM may be beneficial in the treatmentof organophosphate insecticide (OPI) poisoning in sheep(Srivastava et al., 1988). The data on binding of DAM withplasma proteins of goats revealed that at different plasmaconcentrations of 2, 4, 8, 20 and 40 �g ml−1, DAM wasbound with plasma protein to the extent of 50.7–59.4%,respectively, with an overall mean of 54.4% which sug-gested that good percentage of DAM was available in bloodstream for its therapeutic action. It has been reported thatlow to moderate (<80%) extent of protein binding has lit-tle or no influence on kinetic disposition of drug (Pilloid,1973).

Approximately 10.44% of the total administered dosewas eliminated in urine within 24 h. The results of thepresent urinary excretion study suggest that DAM is highlyeliminated from the body by non-renal route. No study was

conducted on the metabolites which might be following arenal route of excretion. Furthermore, slow urinary excre-tion of 2,3-butanedione monoxime seems to be a majorcontributing factor for the longer elimination half-life. Inbuffalo calves also 5–8% cumulative renal excretion of DAM

(�g ml ) (�g ml )

9.60 21.5 4.016.0 32.7 4.026.0 54.0 4.0

was reported after its intravenous administration during24 h (Srivastava, 1984). Higher cumulative renal excretionof DAM (about 16%) has been reported in sheep (Srivastavaand Malik, 1988).

The prime objective of this study was to compute theappropriate dosage schedule of DAM for the treatment ofOPI poisoning in goats. For AChE reactivators, a concentra-tion of 4 �g ml−1 is considered to be adequate therapeuticconcentration (Sidell and Groff, 1971; Sundwall, 1961).Taking different dosage intervals, the priming and main-tenance doses of DAM are calculated (Table 5). On thebasis of the present investigation, it is concluded that themost appropriate dosage schedule of DAM, in the treat-ment of OPI toxicity in goats would be 27.5 mg/kg followedby 25.5 mg/kg at 6 h intervals. For the clinical considera-tion, the loading dose as well as the maintenance dose maybe taken as 28 mg/kg repeated at 6 h intervals.

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