Oral pharmacokinetics of sulfadiazine and sulfamonomethoxine in female Holstein milking cows.

The efficacy of orally administered drugs in cattle is thought to be slow because of the anatomical and physiological features of their forestomach. Thus, parenteral routes are mainly preferred to administer drugs. However, the effect of some drugs with unique physicochemical properties was promptly obtained even after oral administration in clinically ill cattle. Therefore, the present study aimed to investigate pharmacokinetically the usefulness of the oral route in cattle by comparing the oral pharmacokinetic properties of two sulfonamides with different physicochemical properties. Sulfadiazine (SDZ) and sulfamonomethoxine (SMM) were administered by intravenous and oral route to four female Holstein cows with a 4-weeks washout period. Blood samples were collected over time, and SDZ and SMM concentrations in plasma were analyzed by HPLC. Data obtained from the same animal after intravenous and oral administration were simultaneously analyzed with the one compartment model, and kinetic parameters were calculated. The Tmax (mean ± SD) of SMM (2.75 ± 0.96 hr) was significantly achieved earlier than that of SDZ (5.00 ± 1.15 hr). Further, the mean absorption time of SMM (5.24 ± 0.69 hr) was significantly shorter than that of SDZ (5.92 ± 1.11 hr). Also, the half-life of absorption of SMM (3.91 ± 0.51 hr) was significantly shorter than that of SDZ (4.51 ± 0.82 hr). These data suggest that the absorption rates of highly unionized drugs (such as SMM) from the forestomach of cattle may be markedly higher than less unionized ones (such as SDZ).

Determination of sulfamonomethoxine in tilapia (Oreochromis niloticus × Oreochromis mossambicus) by liquid chromatography-tandem mass spectrometry and its application pharmacokinetics study.

A precise and reliable analytical method to measure trace levels of sulfamonomethoxine (SMM) and N4-acetyl metabolite in tilapia samples using liquid chromatography-tandem mass spectrometry was developed. Optimized chromatographic separation was performed on C18 reversed-phase columns using gradient elution with methanol and 5 mmol/L of an ammonium acetate aqueous solution (adjusted to pH 3.5 using formic acid). This study investigated the pharmacokinetic properties and tissue distribution of SMM and its major metabolite N4-acetyl sulfamonomethoxine (AC-SMM) in tilapia after a single dose of 100 mg kg-1 body weight of orally administered SMM. Blood and tissues were collected between 0.5 and 192 h with 14 total sampling time points. SMM was rapidly absorbed, and extensively distributed in the bile and liver through systemic circulation. Enterohepatic circulation of SMM was observed in the tilapia body. Acetylation percentages were 45% (blood), 90% (liver), 62% (kidney), 98% (bile), and 52% (muscle). High concentrations of AC-SMM accumulated in the tilapia bile. At 192 h, AC-SMM concentration in the bile remained at 4710 µg kg-1. The ke value of AC-SMM (0.015 h-1) in the blood was lower than that of SMM (0.032 h-1). This study demonstrated effective residue monitoring and determined the pharmacokinetic properties of SMM and AC-SMM in tilapia.

Oral pharmacokinetics of the acidic drugs, diclofenac and sulfamonomethoxine in male Shiba goats.

In the present study, we examined the oral pharmacokinetics of the acidic drugs, diclofenac (DF) and sulfamonomethoxine (SMM), which have different physicochemical properties, in Shiba goats. DF and SMM were intravenously and orally administered to 5 male goats using a crossover design. The T(max) of DF and SMM were reached 1.5 and 5.6 hr after they have been orally administered, respectively, and this was followed by their slow elimination. The elimination of both drugs was markedly faster after being intravenously rather than orally administered, which indicated flip-flop phenomena after the oral administration. The mean absorption times (MATs) of DF and SMM were 6 and 15 hr, respectively. This slow absorption may have been due to slow gastric emptying in goats. The large difference observed in MATs between DF and SMM may have been because DF, which is more lipophilic than SMM, was partly absorbed from the forestomach. Therefore, these results suggest that the absorption of highly lipophilic drugs from the forestomach may be markedly high in Shiba goats. In case of drugs whose elimination is quite fast, their efficacies may appear from the early stage after oral administration even in ruminants, because elimination rate is the determinant factor of T(max) in flip-flop phenomena. Such drugs may be used orally even in ruminants.

Pharmacokinetics of sulfamonomethoxine in tongue sole (Cynoglossus semilaevis) after intravenous and oral administration.

The pharmacokinetic profiles of sulfamonomethoxine (SMM) were investigated in flatfish tongue soles in the present study. After a single injection of SMM (40 mg/kg BW) to caudal vein of tongue sole at 20 °C, plasma drug concentration versus time data were best fitted to a three-compartment model, characterized with 0.2, 5.7, and 80.4 h for the half-life (t 1/2) of fast distribution, slow distribution, and elimination, respectively. The apparent volume of distribution was 0.1 L/kg, and the body clearance was 0.03 L/h/kg. After oral administration of SMM (200 mg/kg BW) to tongue soles at 20 °C, plasma drug concentrations were best fitted to a two-compartment model, of which the mean half-life of absorption (t 1/2ka) and elimination (t 1/2ß ) were 1.7 and 95.7 h, respectively. The maximal absorption concentration (C max) was estimated as 58 mg/L at 2.5 h, and the mean systemic bioavailability (F) was 39.5 % in tongue soles after oral administration.

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.

Hepatic biotransformation profiles of sulphamonomethoxine in food-producing animals and rats in vitro.

Hydroxylation and acetylation of sulphamonomethoxine (SMM) and deacetylation of N4-acetyl SMM (N4-AcSMM) were estimated in liver post-mitochondrial supernatants (S-9) from laying hens, female cattle, swine and rats. The formation of hydroxylated SMM, 2,6-dihydroxy SMM (2,6-diOH-SMM), was found only with hen S-9s. N4-acetylation rate of SMM was the highest in pig S-9s, followed by rat, then hen or cow S-9s. All S-9s from the four species deacetylated N4-AcSMM. In hen S-9s, the rate of 2,6-dihydroxylation was higher during incubation at 41 degrees C than at 37 degrees C.

Spiramycin, oxytetracycline and sulphamonomethoxine contents of eggs and egg-forming tissues of laying hens.

Spiramycin (SP), oxytetracycline (OTC) or sulphamonomethoxine (SMM) was fed to laying hens at a dietary level of 400 p.p.m. for 7 successive days. After 7 days of medicated feed, the concentrations of SP, OTC and SMM were determined in the blood, liver, ovary, oviducts (magnum and isthmus plus shell gland) and eggs (albumen and yolk) by high-performance liquid chromatography. Of the three drugs, OTC showed the lowest content in the above tissues and eggs, while the reverse was true for SMM. Low concentrations of SP were measured in the blood, whereas contents in the liver and the oviducts were relatively much higher.

Absorbability of sulphamonomethoxine and sulphadimethoxine administered via food of laying hens.

Sulphamonomethoxine (SMM) or sulphadimethoxine (SDM) were fed each to four laying hens at a dietary content of 400 p.p.m. 1000 p.p.m. of chromic oxide were supplemented to the experimental diets as an indicator for the absorbability in the gastrointestinal tract. SMM and SDM contents (p.p.m.) in the large intestine, determined 16 h after the start of feeding, were measured by HPLC. Average amounts of SMM and SDM in the dry matter of the large intestine were 12.3 and 30.2 p.p.m., respectively. The absorption ratios of SMM and SDM administered via the food were calculated to be 96.9 and 92.5%, respectively.

Deacetylation as a determinant of sulphonamide pharmacokinetics in pigs.

Sulphamonomethoxine (SMM), sulphadimidine (SDD), sulphadiazine (SDZ) and their N4-acetyl derivatives (AcSMM, AcSDD and AcSDZ) were intravenously injected into Goettingen miniature pigs and deacetylation was evaluated from plasma concentration-time curves, renal excretion, and rate constants obtained from pharmacokinetic analysis, using a non-linear least-squares method. Deacetylated metabolite was detected in both plasma and urine after intravenous injection of AcSMM, AcSDD and AcSDZ. The area under the curve (AUC) values for the deacetylated metabolite were significantly higher than those for acetyl derivatives after AcSMM and AcSDD administration, but significantly lower after AcSDZ. After AcSMM and AcSDD injection, the concentration ratio between deacetylated metabolite and acetyl derivative was almost constant in the terminal linear phase and similar to that seen after injection of sulphonamide. After AcSDZ injection, however, a constant ratio was not observed. These results indicate that deacetylation can have a significant effect on the pharmacokinetics of SMM and SDD, but not on those of SDZ in pigs. The rate constant for deacetylation was significantly higher than that for acetylation for SMM and SDD, but significantly lower for SDZ. It is, therefore, concluded that deacetylation may be a determinant of the pharmacokinetics of SMM and SDD in pigs. It was, however, not a determinant of SDZ pharmacokinetics because N4-acetylation is not the main elimination route in pigs.

Depletion of dietary sulphamonomethoxine and sulphadimethoxine from various tissues of laying hens.

Sulphamonomethoxine (SMM) or sulphadimethoxine (SDM) was fed to laying hens at 400 mg/kg diet for 5 successive days. After withdrawal of the drugs, contents (mg/kg) of SMM and SDM in the blood, kidney, liver, ovary, muscle and adipose tissue were determined by HPLC. 2. The disappearance of dietary SMM and SDM from the tissues of laying hens was rapid and, except for the liver, was very similar in all tissues. 3. A common biological half-life (t1/2) of SMM in the above 6 tissues was estimated to be 5.2 h. The t1/2 of SDM in the liver was 6.9 h, significantly longer than that of 4.4 h in the other 5 tissues. The values were much shorter than 51/2 (reported elsewhere) for other drugs. 4. Comparing the data found in this study with those obtained from previous papers, the depletion velocities of SMM and SDM from the hen's body were much faster than those from albumen in egg. The reason for this is probably related to the longer time period over which albumen formation occurs.

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.

Transfer of dietary sulphamonomethoxine and sulphadimethoxine into various tissues of laying hens.

1. Sulphamonomethoxine (SMM) or sulphadimethoxine (SDM) were fed to laying hens at a dietary concentration of 400 mg/kg. Concentrations (mg/kg) of SMM and SDM in the blood, kidney, liver, ovary, muscle and adipose tissue, collected at 4, 8, 16 and 24 h after the start of feeding, were determined by HPLC. 2. The relationships between the sulphonamide concentrations (mg/kg) in the tissues and times (h) after the start of the feeding were analysed statistically. 3. Dietary SMM and SDM were transferred throughout the whole body, and concentrations in all tissues became constant 8 h after the start of feeding. 4. Among the 6 tissues examined the constant values (mg/kg) of both SMM and SDM were highest in the kidney and were lowest in adipose tissue. 5. With the exception of adipose tissue, the values of SDM in the tissues were statistically greater than those of SMM.

Pharmacokinetic profile of sulphamonomethoxine-trimethoprim in horses after intravenous, intramuscular and oral administration.

The pharmacokinetic profile of a sulphamonomethoxine-trimethoprim (SMM-TMP) combination was investigated in five horses. The combination was administered intravenously, intramuscularly and orally at a constant dose of 20 mg SMM plus 4 mg TMP kg-1 bodyweight. Following intravenous administration both drugs dispersed rapidly with distribution half-lives of about 12 minutes for SMM and about 18 minutes for TMP. Elimination half-lives for intravenous, intramuscular and oral administration were closely similar, indicating that elimination was independent of administration route. Bioavailability of the drugs in aqueous solution was good: about 72 per cent and 84 per cent for SMM and about 84 per cent and 98 per cent for TMP following intramuscular and oral administration, respectively. It is concluded that SMM-TMP administered orally once a day at 20 mg and 4 mg kg-1 bodyweight, respectively, maintains therapeutic concentrations, whereas twice daily intramuscular administration would be more effective for treating systemic infections in the horse than the once a day regimen usually adopted in veterinary practice.

Pharmacokinetics and acetylation of sulfa-2-monomethoxine in humans.

In humans sulfa-2-monomethoxine (S) is metabolized by N4-acetylation (39.9 +/- 8.0 per cent). After an oral dose, S is eliminated biphasically (t1/2, 5.2 +/- 1.6 h and 13.2 +/- 3.4 h) which is similar in both fast and slow acetylators. The metabolite N4-acetylsulfa-2-monomethoxine (N4) is eliminated monophasically (t1/2, 30.0 +/- 5.7 h). The intrinsic mean residence time (MRT) of N4 is 33.5 +/- 8.8 h. The mean total body clearance of S is 11.6 +/- 2.7 ml min-1, and the Vdss is 12.3 +/- 1.01. The renal clearance of S during the first day was twice as high as on the following days for two of the six volunteers (8 vs 4 ml min-1). The renal clearance of N4 during the first day, for four out of the six volunteers, was twice as high as on the following days (8 vs 4 ml min-1). The protein binding of S is 95 per cent and that of its conjugate N4 98 per cent. Approximately 80 per cent of the oral dose of S is excreted in the urine as parent drug (41.0 +/- 6.2 per cent) and as N4 acetyl conjugate (39.9 +/- 8.0 per cent).

O-Dealkylation and N4-acetylation of sulpha-2-monomethoxine by the turtle Pseudemys scripta elegans.

Sulpha-2-monomethoxine is N4-acetylated to an extent of 12% of the dose by Pseudemys scripta elegans; 48% is excreted unchanged. No O-dealkylation of the 2-methoxy group takes place.

Pharmacokinetics, N1-glucuronidation, and N4-acetylation of sulfa-6-monomethoxine in humans.

Sulfamonomethoxine (S) is metabolized by O-dealkylation, N4-acetylation, and N1-glucuronidation. In humans, only N1-glucuronidation (12%) and N4-acetylation (36%) takes place. The N1-glucuronide is directly measured by HPLC. When N4-acetylsulfamonomethoxine (N4) is administered as the parent drug, N1-glucuronidation does not occur. After an oral dose, fast and slow acetylators show a similar t1/2 for S (25.0 +/- 4.6 hr vs. 29.8 +/- 4.8 hr; p = 0.459), and the t1/2 of the N4-acetyl conjugate is also similar in fast and slow acetylators (25.0 +/- 4.64 hr vs. 29.8 +/- 4.8 hr, p = 0.459). The intrinsic mean residence time of N4 is 7.1 +/- 2.3 hr. The mean total body clearance of S is 5.0 +/- 1.3 ml/min, the renal clearance is 0.84 +/- 0.26 ml/min, and the volume of distribution at steady state is 11.7 +/- 3.4 liters. The renal clearance of N4 is 17.89 +/- 4.19 ml/min. No measurable concentrations of the N1-glucuronide of S are found in plasma. The protein binding of S is 92%. N1-glucuronidation results in an 80% reduction in the protein binding of S (11%). N4 shows a high protein binding of 98%. Approximately 60% of the oral dose of S is excreted in the urine.

Blood kinetics of sulfamonomethoxine and oxytetracycline following intrauterine spray injection in dairy cows.

Intrauterine administration was performed in six Friesan cows with a disposable spray preparation containing 3 g of sulfamonomethoxine and 3 g of oxytetracycline, in order to investigate their serum kinetics. Sulfamonomethoxine levels were determined by a reversed-phase HPLC method, whilst oxytetracycline quantities were detected by a microbiological method. The sulphonamide had a peak 1.17 h after the administration, the tetracycline reached its highest concentration after 8 h. The bioavailability of both drugs was low and detectable drug amounts were no longer recovered after 24 h.

Oxidation and O-dealkylation of sulphamonomethoxine by the turtle Pseudemys scripta elegans.

Sulphamonomethoxine is O-demethylated at the 6 position and oxidised at the 2 position of the pyrimidine substituent by Pseudemys scripta elegans. No N4-acetylation takes place. The yield of the oxidation reaction is twice that of the O-demethylation reaction.

An appropriate ingestion volume of oral sulfa drug suspension in pigs.

The influence of ingested volume of a sulfa drug suspension, sodium sulfamonomethoxine (SMMNa), on the oral pharmacokinetics was studied in pigs, with regard to bioavailability and gastric emptying. Eighteen pigs, weighing 30-70 kg, were used. Phenol red solution was used for the evaluation of gastric emptying study. SMMNa suspension was used for pharmacokinetic study. Both of these fluids were administered by natural swallowing. Three experimental groups were constructed: G-I; 5 ml/kg of the test fluids to starved animals, G-II; 5 ml/kg of the test fluids to fed animals and G-III; 20 ml/kg of the fluids to fed animals. The glucose glycine electrolyte solution (GGES) was used as the vehicle for both the compounds. Six pigs, having duodenal cannula, were used for the study of gastric emptying. The gastric emptying rate was rapid in G-I, relatively rapid in G-III, and slow and variable in G-II. In agreement with the result of gastric emptying study, the values of Cmax and tmax were high and rapid in G-I, relatively high and rapid in G-III, and low and slow in G-II. Accordingly, the voluminous ingestion of drug suspension can facilitate the gastric emptying, in turn may make the oral absorption of the drug rapid-and-uniform. The 20 ml/kg volume of sulfa drug suspension may practically be recommended for the oral administration in pigs.