Kinetic modelling and residue depletion of drugs in eggs.

1. A physiologically-based pharmacokinetic model was developed for the purpose of describing the relationship between plasma concentration of drugs and their deposition into eggs. 2. By incorporating the physiology of egg formation into the model, the transfer of drugs into the egg albumen and yolk could be described using rate constants. 3. The model was used to describe concentrations in albumen and yolk of sulphanilamide, sulphaquinoxaline and pyrimethamine as a function of time using datasets from the literature. 4. The model could be used as a tool to obtain an insight into those properties of a drug which are responsible for the amount of residue in eggs, and could help in the design of critical studies for determining withdrawal periods for eggs.

Determination of residues of sulphonamide in eggs and laying hens.

Eggs were collected from different areas of Faisalabad city. The quantity of sulphonamides was determined in yolk, white and whole egg and compared with the permissible limit 1 microg/ml for sulphadimethoxine available in literature. In another experiment, a group of hens were kept at a poultry farm after medicating them with darvisal liquid to see if the residues of sulphonamide pass into the eggs of poultry. The period of existence of residues was noted.

Determination of 14C residue in eggs of laying hens administered orally with [14C] sulfaquinoxaline.

Ten layer hens were dosed for 5 consecutive days with 6.2 mg kg(-1) [14C] sulfaquinoxaline (SQX). Eggs were collected from the hens during the 5-day dosing period and during a 10-day post-dose withdrawal period. Egg yolk and albumen were separated and assayed for total radioactive residues (TRR) using a combustion oxidizer and liquid scintillation counting techniques. Significant amounts of radioactivity were detected on the second day of dosing (greater than 24h after the initial dose) in both egg yolk and albumen. First eggs were collected about 8 h after dosing; the second-day eggs were collected during 8-h period after the second dose. Radioactive residues reached a maximum on the fifth day of dosing in albumen, whereas on the second day of withdrawal in egg yolk, the peak TRR levels in albumen were about threefold higher than in yolk. Thereafter, the TRR levels declined rapidly in albumen and were detectable up to withdrawal day 6, whereas the TRR levels in egg yolk declined more slowly and were detectable up to withdrawal day 10. High-performance liquid chromatography analysis indicated that the parent drug sulfaquinoxaline was the major component in both the egg albumen and yolk. Additionally, this work suggests that egg yolk is the appropriate matrix for monitoring SQX residues

Binding profile of spiramycin to oviducal proteins of laying hens.

In vitro protein binding of spiramycin (SP) in the plasma and oviducts of laying hens was studied. The data for SP were compared with those for oxytetracycline (OTC), sulphadimidine (SDD), sulphamonomethoxine (SMM) and sulphaquinoxaline (SQ). The two oviduct segments, magnum (M) and isthmus plus shell gland (IS), were collected. The soluble (cell sap) fractions from the magnum (M-S9) and the isthmus plus shell gland (IS-S9) were used as samples. Plasma protein binding was highest for SQ (81.4%) (P < 0.01), and lowest for SDD (30.9%) (P < 0.01). No M-S9 protein binding of OTC was found. The IS-S9 protein binding of SP (60.4%) was very much higher than those of OTC (0.8%), SDD (4.1%), SMM (4.0%) and SQ (12.3%) (P < 0.01). Biological half-lives of these drugs in egg albumen were directly correlated to the extent of their binding to IS proteins. Of plasma, M-S9 and IS-S9, variation in SP concentration in the ranges from 1 to 20 micrograms/ml did not alter the binding properties of the drug.

Tissue residues of some sulphonamides in normal and Eimeria stiedai infected rabbits.

Tissue residues of sulphadiazine (SDZ), sulphadimidine (SDD) and sulphquinoxaline (SQ) were studied in healthy and E. stiedai infected rabbits following oral administration of 0.5 g/l drinking water for 5 days. The solid-phase extraction and HPLC was used to determine the concentration of the three sulphonamides in a single tissue sample. SDZ was detected in the liver and kidney in concentrations below the tolerance levels at day 5 and no residues could be detected at day 7 after drug withdrawal. SDD and SQ were detected in all of the tested organs of healthy rabbits up to day 5, where the highest concentration was reported in the liver (0.08 +/- 0.02 and 0.09 +/- 0.02 g/g respectively). In infected rabbits, the three sulphonamides were detected up to day 7 in concentrations higher than the tolerance limits (> 0.1 g/g) in the liver and kidney and lower levels in other tissues. A withdrawal period of 4 days for SDZ and 5 days for SDD and SQ in healthy rabbits and 7 days for SDZ and 8 days for SDD and SQ in E. stiedai infected rabbits is suggested.

Transferring profile of dietary sulphaquinoxaline into eggs.

Sulphaquinoxaline (SQ) was fed to laying hens at the dietary levels of 25, 50, 100 and 200 ppm, respectively, for 7 successive days. The increasing amount of SQ transferred into the whole egg during SQ feeding could be well described by the following equation: [equation: see text] where y is the SQ content (ppm) in the whole egg, x is the dietary SQ level (ppm), T is days on SQ feeding (T < or = 4). After 4 days of SQ feeding, the SQ content in the homogenized eggs reached a plateau at 0.0292.x (= 0.007318.4x) ppm. This equation permits to predict SQ content in the eggs.

Decreasing profile of residual sulphaquinoxaline in eggs.

1. Sulphaquinoxaline (SQ) was added to the diet of laying hens at 200 mg/kg for 7 successive days. Contents (mg/kg) of SQ in albumen and egg yolk of eggs laid after drug withdrawal were determined by high pressure liquid chromatography (HPLC). The contents in the whole egg were calculated taking into consideration the respective weights of albumen and egg yolk. 2. A time-lag in the initiation of decrease of SQ from eggs after the withdrawal of dietary SQ was observed. 3. The decreasing pattern from whole egg could be well described by the following equation with a time-lag of 1.0 d, y = 2.07 e-0.5620(t-1.0), where y is the SQ content in whole egg, t is time (d) after the withdrawal of dietary SQ and a constant of 2.07 is the SQ content in whole egg laid at the withdrawal. 4. Biological half-life of SQ in the whole egg was estimated to be 1.23 d. 5. From the above equation, SQ residue of whole egg laid at 9th d after withdrawal will be below the detection limit of 0.01 mg/kg.

Tissue concentrations of sulphaquinoxaline administered in the food of laying hens.

1. Sulphaquinoxaline (SQ) was fed to laying hens at a dietary level of 400 mg/kg for 3 successive days. SQ contents (mg/kg) in the blood, kidney, liver, ovary, muscle (thigh) and adipose tissue collected on 1, 2, and 3 d after the start of feeding were determined by HPLC. The relationship between the SQ content in the tissues and times (d) of SQ feeding was analyzed statistically. 2. Dietary SQ was distributed throughout the whole body. 3. Contents in tissues, except the kidney, had already reached a plateau by day 1 after the start of administration whereas in the kidney it increased linearly throughout the 3 days. 4. The plateau values of SQ in the tissues were much greater than those of sulphamonomethoxine and sulphadimethoxine.

Kinetic behaviour of sulphaquinoxaline and amprolium in chickens.

The pharmacokinetics of sulphaquinoxaline and amprolium hydrochloride were studied in Hubbard broiler chickens. Single doses of sulphaquinoxaline (100 mg/kg b. wt.), and amprolium hydrochloride (30 mg/kg b. wt.) were administered orally and intravenously to the same birds with 15 days interval between treatments. Sulphaquinoxaline and amprolium HCl were determined colorimetrically. Following i.v. administration, the concentration-time curve of sulphaquinoxaline and amprolium could be explained by a two compartments open model with a t1/2 alpha of 0.16 +/- 0.008 h; 0.17 +/- 0.09 h; t1/2 beta of 12.6 +/- 0.32 h, 4.89 +/- 0.3 h respectively. The total body clearance were 0.278 +/- 0.013 ml/kg/min; 0.562 +/- 0.015 ml/kg/min; volume of distribution at steady state were 0.44 +/- 0.009 L/kg, 0.34 +/- 0.005 L/kg and systemic bioavailability following oral administration were 72.65 +/- 3.38, 66.09 +/- 4.9 percent for sulphaquinoxaline and amprolium HCl respectively. Following oral administration of sulphaquinoxaline and amprolium (the same previous doses) the peak plasma concentrations (Cmax) were 107.8 +/- 1.49 micrograms/ml; 42.9 +/- 1.11 micrograms/ml and occurred at 5.56 +/- 0.1 h, 3.67 +/- 0.05 h respectively. Pharmacokinetic parameters after repeated oral daily administrations of sulphaquinoxaline and amprolium revealed that the Cmax was 184 +/- 1.02 micrograms/ml, and 55.19 +/- 0.35 micrograms/ml at 7.36 +/- 0.18 h and 5.17 +/- 0.15 h and the biological half lives were 1.67 +/- 0.057 h and 1.11 +/- 0.14 h respectively. Sulphaquinoxaline and its N4 acetyl metabolite disappeared from all body tissues at 120 hours, however amprolium persisted in most tissues for 72 hours after the last dose of repeated administrations.

Comparative plasma and tissue pharmacokinetics and drug residue profiles of different chemotherapeutants in fowls and rabbits.

Blood and tissue pharmacokinetics and drug residue profiles of six chemotherapeutants were studied. Ceftriaxone (CEF), intravenously at 50 mg/kg, sulfamonomethoxine (SMM) and sulfaquinoxaline (SQ), orally at 200 mg/kg, and olaquindox (OLA), orally at 50 mg/kg, were administered to young broilers. Penicillin (PEN), intramuscularly at 200,000 U/kg, and albendazole (ALB), orally at 20 mg/kg, were given to rabbits. For each drug, 13-18 groups (n = 5-10 individuals/group) of the dosed animals were killed at different post-dosing times. Drug and/or metabolite concentrations in plasma, liver, kidney, heart, lung, and muscle tissues were analysed by HPLC procedures. Multi-exponential kinetic models were fitted to the observed tissue concentration-time data by applying a non-linear least-squares regression computer program. Tissue half-life, peak tissue concentration, and time of peak tissue concentration were determined. Half-life of CEF, SMM, SQ, OLA, PEN, ALB, and two metabolites of ALB (sulfoxide and sulfone) in various tissues ranged 0.6-1.4, 4.7-9.0, 4.5-18.9, 1.8-3.1, 0.9-3.0, 3.4-9.6, 5.0-16.1 and 7.4-12.2 h. The times required for CEF, SMM, SQ, OLA, PEN, and ALB residue concentrations to decline to 0.1 microgram/g in various tissues ranged from 5.0-11.6, 70.0-110.5, 114.0-179.8, 21.3-30.3, 4.1-24.8 and 47.8-84.4 h. Drug kinetic characteristics in tissues differed significantly from those in plasma, and also varied from tissue to tissue. It is necessary, therefore, to evaluate tissue kinetics when designing dosage regimens in tissue infection chemotherapy with these drugs. Knowledge of tissue kinetics is also important in predicting and controlling drug residues in edible tissues of food-producing animals.

Coccidiosis: a radiological study of sulphaquinoxaline distribution in infected and uninfected chickens.

Using scintillation counting and autoradiographical techniques, the whole-body distribution in week-old uninfected chickens of the anticoccidial agent sulphaquinoxaline (SQ) labelled with 35S was established at various time intervals after a single oral dose either alone or following continuous in-feed medication with unlabelled SQ, and after a single intravenous dose. The distribution was also established in chickens infected with the coccidia Eimeria acervulina or E. tenella, after a single oral dose of radiolabelled SQ administered either alone or following continuous in-feed medication with unlabelled SQ, as for uninfected chicks. In all uninfected chicks, SQ was rapidly absorbed from the gut and was distributed to all tissues. It appeared at high concentrations in the bile and kidneys 0.5 h after dosing. In chickens that had previously received unlabelled SQ in the diet, a radiolabelled dose maintained steadier tissue concentrations than the sharp rise and fall detected after a single oral dose. Intravenous dosing of uninfected chicks showed that SQ was secreted by the crop, gizzard and caecal epithelia into their lumina. Infection with E. acervulina or E. tenella coincided with an overall 3.5-fold sustained increase of SQ concentration in chick tissues. An updated hypothesis including these new observations for the anticoccidial mode of action of SQ in chickens is expounded.

Interaction between lead toxicity and some sulphonamides in rabbits: effect on certain blood constituents and serum enzymes.

Two main equal groups of clinically healthy, non pregnant rabbits were classified into 4 subgroups (5 rabbits each). The 1st and 2nd subgroups were treated with sulphaquinoxaline or sulphadiazine in a single oral dose of 100 mg/kg b. wt., while the 3rd and 4th subgroups received a repeated oral dose of 100 mg/kg b. wt., daily for 5 successive days, respectively. The second main group received lead acetate in a dose of 4.2 mg/kg b. wt. per day for 2 months, then was classified as in case of the 1st main group and administered the respective sulphonamides in their recommended doses. The experimental lead intoxication was found to decrease the free delta-aminolevulinic acid dehydratase (delta-ALA-D) activity in blood of lead intoxicated rabbits after 4 and 8 weeks. Also, the ratio of free and with glutathione reactivated delta-ALA-D was increased 2.9 and 2.2 after 4 and 8 weeks, respectively as compared with before lead administration (1.19), indicating toxicity. The sulphonamide/creatinine ratio was increased after administration of both sulphonamides but higher in lead intoxicated rabbits as compared with healthy ones. The AST/ALT ratio was decreased 4 and 8 weeks after lead exposure. The AST, ALT and AST/ALT ratio, alkaline phosphatase, urea and creatinine were not altered in healthy rabbits. Repeated oral administration of sulphadiazine caused a significant increase in serum AST, ALT, alkaline phosphatase and creatinine level in healthy and lead intoxicated rabbits. On the other hand, AST/ALT ratio in both healthy and lead intoxicated rabbits was found to decrease 1 h after the last dose as compared with before treatment.

Tissue sulfonamide concentration and correlation in turkeys.

Nineteen hen turkeys (10 to 12 kg each) were used in a feeding study to determine sulfadimethoxine and sulfaquinoxaline concentrations in blood serum, liver, and skeletal muscle, as well as the respective ratios at selected withdrawal intervals. Two feeds were prepared by use of premixes to achieve 60 mg of sulfadimethoxine/kg and 100 mg of sulfaquinoxaline/kg, respectively. Each of the medicated feeds was given to 9 turkeys for 7 days. The turkeys were then fed nonmedicated feed at intervals from 24 to 56 hours and were slaughtered. One turkey was used as control. The serum/liver and serum/muscle ratios for sulfaquinoxaline were 60 to 70% higher than for sulfadimethoxine. However, the liver/muscle ratio for both sulfonamides was equivalent, approximately 3. Disposition of both sulfonamides approximated first-order pharmacokinetics. The calculated half-life of sulfadimethoxine was half that of sulfaquinoxaline, approximately 16 vs 30 hours. The coefficients of variation in the serum/tissue ratios for both sulfonamides were between 13% and 25% for serum/liver and less than 15% for serum/muscle, indicating excellent potential for using serum as a predictor of actionable concentrations of sulfonamide residues.