Serum disappearance and urinary excretion of sulfamethoxypyridazine in goats = Desaparicion sérica y excrecion urinaria de la sulfametoxipiridazina en cabras= Disparition sérique et excrétion urinaire de la sulfaméthoxypyridazine chez la chèvre

La pharmacocinétique et l’excrétion urinaire de la sulfaméthoxypyridazine ont été déterminées sur des chèvres après une injection unique par voie intraveineuse à la dose de 100 mg/kg de poids vif. Un modèle ouvert à deux comnartiments aaoaraît comme le mieux adapté uour décrire la cinétiqtk de l’élimiuãtion du produit. Sa distributi& et son élimination an stade de la demi-vie ont été de 0,lO + 0,03 et de 6.28 f 0.44 h. resoectivement. Les valeurs du volume aauarent de la

tic data obtained in the pat-ticular animal species and the environment in which the drug is ,to be clinically used.Data are available on the pharmacokinetics of a number of sulfonamides in goats (11,12,16).However, such informations on the disposition kinetics and urinary excretion of SMPd are apparently lacking in goats.This investigation was undettaken to determine the disposition kinetics, suitable dosage regimen and urinary excretion of SMPd in this species.

INTRODUCTION
Pharmacokinetic studies This study is a part of an applied research project to recommend an efficient sulfonamide which does not require frequent administration in goats, at least not earlier than 12 hours, a period under which it would be practically unfeasible in field conditions.

Sulfamethoxypyridazine
(SMPd), a long acting sulfonamide, is gaining wide acceptance in the armament of antimicrobial therapy in veterinary medicine.Studies on the blood/plasma levels and/or blood disposition of SMPd in different species of animals namely sheep (8,15), calves and cattle (4, 14, 15), buffalo calves (13), swine (5, 7) and dogs and horses (15) and the data on its urinary excretion in sheep (8), pigs (7) and buffalo calves (13) revealed inter-species variation in the degree of acetylation, pharmacokinetic profile and urinary excretion.The optimal therapeutic regimen should be based on the kine-SMPd (25% solution)* was administered intravenously (IV) to four animals at the dose rate of 100 mg/kg body weight.Blood samples (4 ml each) were drawn from the contralateral jugular vein at 2.5, 5, 10, 20 and 40 min and 1, 1.5, 2, 4, 6, 8, 12, 24, 48 and 72 post injection hour.Serum was separated and stored at -20°C until analysis.

Urinary excretion
Urinary excretion studies were conducted in five goats following a single IV dose of 50 mg/kg body weight.The animals were kept in metabolic cages of standard size.With the help of urine collecting bags, the total volume of urine voided during O-3, 3-6, 6-9, 9-12 and 12-24 h was collected and recorded.An aliquot was taken, centrifuged and stored at -20°C until analysed for SMPd.after acid hydrolysis with 0.5 N HCI for 1 h.The percentage of acetylation was calculated by the following formula: where N, and S are the concentrations of acetylated and free SMPd, respectively.

Pharmacokinetic analysis
The serum SMPd concentrations against different time intervals from individual goat were analysed by using the curve-stripping (CSTRIP), which determines whether data cari best be described by mono-, bi-or triexponential equations, and the nonlinear least square regression (SASNONLIN) computer programmes.
After fitting the data to a suitable biexponential equation, other pharmacokinetic parameters were determined as described by BAGGOT (1) and GIBALDI and PERRIER (6).

Dosage regimen
On the basis of in vitro minimum inhibitory concentrations (MIC) of 2 25 pg/ml in respect of majority of the microorganisms ( 9) and the disposition kinetic data, the dosage regimen were calculated by using the equation as described by NOTARI (10).

RESULTS
The data on serum concentrations (mean f SEM) of free and the N,-acetyl-metabolite of SMPd as a function of time in goats are presented in table 1.The peak serum concentration of 414.37 f 23.94 pg/ml observed at 2.5 min declined rapidly to 312.15 ug/ml at 10 min.Thereafter, the blood level was reduced gradually to 33.51 pg/ml at 24 h and traces of the drug could be detected in blood up to 72 h.
No definite pattern of acetylation could be appreciated during the first 6 h, thereafter the percentage of acetylation increased up to 12 h and decreased 12 h onward (table 1).The values of acetylation ranged between 4.49 to 25.07 percent at 2.5 min to 12 h with an overall mean of 11.99 f 1.66 percent during 24 post injection hour.

Different pharmacokinetic
variables describing the distribution and elimination of SMPd in goats are presented in Table II.The distribution and elimination half life values were 0.10 f 0.03 and 6.28 f 0.44 h, respectively.

Parameters determined :
A, a, t,Ja) : intercept, rate constant and half life during the distribution phase, respectively  Table III presents the data (mean f SEM) on urinary excretion of free and N,-acetyl derivative of SMPd after a single IV dose of 50 mg/kg body weight.Urinary excretion pf this drug was almost negligible as only 2.97 f 0.50 percent of the total administered dose was excreted in urine (free + N,-acetyl-metabolite) during 24 h.However, the acetylated metabolite increased from 7.39 f 2.28 percent at 3 h to 27.63 f 7.16 percent by 24.
Calves on the contrary are fast but also poor acetylators (4) and there is no acetylation in dogs (15).

DISCUSSION
Following a single intravenous administration of SMPd, therapeutic concentrations (2 25 pg/ml) were detected in serum up to 24 h.Apparently no data are available on the metabolism of SMPd in goats, however, hydroxylation and glucoronidation have been suggested as the major metabolic pathways for sulfadimidine, and acetylation plays a minor rote (11).Further, goats have been recognized as poor and slow acetylators of sulfadimidine (12,16).
The present studies on the acetylated metabolite in blood and urine suggest that Gaddi goats are slow and poor r l Evaluation of the disposition kinetic data on SMPd revealed that biexponential equation was best suited to describe the pharmacokinetics of this drug in goats as for several other sulfonamides in this species (12,16).The distribution half life (0.10 + 0.03 h) of this drug in goats suggested that this drug is distributed in the body at a much faster rate compared to other sulfonamides -sulfacetamide (0.18 f 0.04 h), sulfadimidine (0.24 -0.80 h) and sulfanilamide (0.23 f 0.03 h), respectively (12).The values of apparent volume of distribution (Vd,,; 0.39 + 0.02 I/kg) reflected slight to moderate degree of penetration of the drug into body fluids and tissues of goats.Almost similar values for the distribution volume have been reported for sulfadimidine, sulfadoxine, sulfamethoxydiazine (16).But higher values of Vd for sulfanilamide, sulfasomidine, sulfadimethoxine and sulfamoxole and on the contrary lower Vd values for sulfamonomethoxine and sulfafurazole have been observed in goats (12,16).
SMPd is distributed almost equally between the central and tissue compartments as reflected by the values of certain pharmacokinetic parameters (T/C -0.99 f 0.13; KldK21 -0.96 + 0.13 ; fc-0.50 f 0.03) and suggested that the disappearance of parent compound from the blood and tissues occurs at similar rates as reported by BEVILL for other sulfonamides in cattle, sheep and swine (2).

'
: mean t Stlvl of four anlmaa ; o : mean _t StM ot three arumals.B, B, t,,&B) : intercept, rate constant and half life during the elimination phase, respectively CP, : expected theoretical drug concentration at time ~ zero Kel : rate constant of elimination from central compartment K,,, K,,: rate constants of transfer of drug from central to peripheral and pheripheral to central compartments, respectively UC, 'Jdss : apparent volume of central compartment and apparent volume of distribution at steady state, respectively CI, : the total body clearance l fc : fraction of the drug present in the central compartment T/C: ratio of drug concentration between tissue and central compartment AUC : area under the concentration -time curve MRT : mean residence time.

TABLE I
Mean concentrations (,ug/ml) of free SMPd and the

TABLE II
Pharmacokinetic parametersfor sulfamethoxypyridazine after a single IV administration (100 mg/kg) in acetylators of SMPd similar to that reported for swine (5).