Pharmacokinetics of sulphanilamide and its three acetyl metabolites in dairy cows and calves

Summary

An intravenous low dosage of sulphanilamide (SAA) (14.0 mg/kg) to 6 pre‐ruminant calves revealed a biphasic SAA plasma disposition with a mean elimination half‐life of 4.1 h. The main metabolite in plasma was N₄‐acetylsulphanilamide (N₄), which 4 hours after injection exceeded the parent SAA plasma concentration. Urinary recovery of SAA was 10 to 16% of the dose; of N₄, it was at least 69%. Traces of the N₁‐acetyl (N₁) metabolite and the doubly acetylated derivative (N₁N₄) were present in urine. The renal clearances of the N₁ and N₄ metabolites showed a tubular secretion pattern, which was at least 2 to 6 times higher than that of SAA.

A single high oral SAA dose of 200 mg/kg to 3 dairy cows resulted in extensive metabolism of SAA into N₄ N₁, and N₁N₄ metabolites; their mean maximum plasma concentrations were 64, 48, 0.72 and 24 μg/ml, respectively. The mean disposition half‐life of SAA in plasma and milk was 10 h. In milk the metabolite concentrations exceeded those in plasma; the N₄ and N₁N₄ metabolite concentrations in milk exceeded that of SAA. The mean maximum concentrations of SAA, N₄, N₁, and N₁N₄ in milk were 52, 89, 2.3, and 98 pg/ml. respectively. For SAA and its metabolites, the binding to plasma and milk proteins was determined. No glucuronide or sulphate conjugates of SAA and its acetyl metabolites could be found in plasma, milk, or urine.

Based on the sensitivity of the bioassay (0.2 μg SAA/ml), a withholding time of 5 days was suggested for milk following single oral SAA dosage of 200 mg/kg.     

Dose dependent disposition of sulphadimidine and of its N4-acetyl and hydroxy metabolites in plasma and milk of dairy cows

The disposition of sulphadimidine (SDM) and of its N4-acetyl (N4-SDM) and two hydroxy metabolites, 6-hydroxymethyl-(SCH2OH) and 5-hydroxyasulphadimidine (SOH), was studied in plasma and milk of dairy cows following intramuscular or intravenous administration of sulphadimididine-33.3% at doses of 10, 45, 50, and 100 mg/kg. The main metabolite in plasma as well as in milk was SCH2OH. The metabolite percentages, the final plasma elimination half-lives, and the time of peak SDM concentrations in milk are presented for different dosages. The concentrations of SDM and its metabolites in milk ran parallel to those in plasma beyond 4 hours p.i. The metabolite concentrations in plasma and milk were lower than those of the parent SDM. Sulphate and glucuronide metabolites could not be detected in milk. At high doses (45 mg/kg or more) and SDM plasma concentrations exceeding 20 micrograms/ml, a capacity limited metabolism of SDM to SCH2OH was noticed, viz. a steady state concentration of SCH2OH and a biphasic elimination pattern for SDM and SCH2OH in plasma and milk. The mean ultrafiltrate ratios of the milk to plasma concentrations with respect to SDM, SCH2OH, SOH, and N4-SDM were: 0.69, 0.22, 020, and 0.63, respectively. The total amount of SDM and its metabolites recovered from the milk after milking twice daily over the whole experimental time was less than 2% of the applied dose. A bioassay method allowed of detecting qualitatively SDM concentrations exceeding 0.2 micrograms/ml in plasma or milk. Withholding times for edible tissues and milk are suggested.     

Pharmacokinetics and bioavailability of cephalothin in horse mares

The pharmacokinetics and bioavailability of cephalothin given to 6 horse mares at a dosage level of 11 mg/kg of body weight IV or IM were investigated. The disposition of cephalothin given IV was characterized by a rapid disposition phase with a mean half-life of 2.89 minutes and a subsequent slower elimination phase with a mean half-life of only 14.7 minutes. The mean residence time of cephalothin was 10.6 +/- 2.11 minutes. The total plasma clearance of cephalothin averaged 13.6 ml/min/kg and was caused by metabolism and renal elimination. Renal clearance of cephalothin averaged 1.32 ml/min/kg and accounted for elimination of about 10.1% of the administered dose. The volume of distribution at steady state averaged 151 mg/kg. Plasma protein binding of cephalothin at a concentration of 10 micrograms/ml averaged 17.9 +/- 2.5%. Cephalothin was rapidly metabolized to desacetylcephalothin. Maximum plasma desacetylcephalothin concentrations were observed in the blood samples collected 5 minutes after IV doses and averaged 22.9 micrograms/ml. The apparent half-life of desacetylcephalothin in plasma was 41.6 minutes and its renal clearance averaged 4.49 +/- 2.43 ml/min/kg. An average of 33.9% of the dose was recovered in the urine as desacetylcephalothin. The maximum plasma cephalothin concentration after IM administration was 11.3 +/- 3.71 micrograms/ml. The terminal half-life was 47.0 minutes and was longer than the half-life after IV administration. The bioavailability of cephalothin given IM ranged from 38.3% to 93.1% and averaged 65.0 +/- 20.5%.     

Pharmacokinetics of probenecid and the effect of oral probenecid administration on the pharmacokinetics of cefazolin in mares

The pharmacokinetics and bioavailability of probenecid given IV and orally at the dosage level of 10 mg/kg of body weight to mares were investigated. Probenecid given IV was characterized by a rapid disposition phase with a mean half-life of 14.0 minutes and a subsequent slower elimination phase with a mean half-life of 87.8 minutes in 5 of 6 mares. In the remaining mare, a rapid disposition phase was not observed, and the half-life of the elimination phase was slower (172 minutes). The mean residence time of probenecid averaged 116 minutes for all 6 mares and 89.2 minutes for the 5 mares with biphasic disposition. The total plasma clearance of probenecid averaged 1.18 +/- 0.49 ml/min/kg, whereas renal clearance accounted for 42.6 +/- 9.3% of the total clearance. The steady-state volume of distribution of probenecid averaged 116 +/- 28.2 ml/kg. Plasma protein binding of probenecid was extensive, with 99.9% of the drug bound at plasma probenecid concentrations of 10 micrograms/ml. The maximum plasma probenecid concentration after 10 mg/kg orally averaged nearly 30 micrograms/ml. The half-life of probenecid after oral administration was approximately 120 minutes. Oral bioavailability was good with greater than 90% of the dose absorbed. The effect of probenecid on tubular secretion of organic anions was evaluated by determining the pharmacokinetics of IV cefazolin (11 mg/kg) administered alone and 15 minutes after probenecid (10 mg/kg orally). Treatment with probenecid did not affect pharmacokinetic values of cefazolin. This failure of probenecid to alter the pharmacokinetics of cefazolin may be caused by insufficient plasma probenecid concentrations after the oral dose.     

Dose dependent disposition of sulphadimidine and of its N4‐acetyl and hydroxy metabolites in plasma and milk of dairy cows

Summary

The disposition of sulphadimidine (SDM) and of its N₄‐acetyl (N₄‐SDM) and two hydroxyl metabolites, 6‐hydroxymethyl‐ (SCH₂OH) and 5‐hydroxyasulphadimidine (SOH), was studied in plasma and milk of dairy cows following intramuscular or intravenous administration of sulphadimididine‐33.3% at doses of 10, 45, 50, and 100 mg/kg. The main metabolite in plasma as well as in milk was SCH₂OH. The metabolite percentages, the final plasma elimination half‐lives, and the time of peak SDM concentrations in milk are presented for different dosages. The concentrations of SDM and its metabolites in milk ran parallel to those in plasma beyond4 hours p.i. The metabolite concentrations in plasma and milk were lower than those of the parent SDM. Sulphate and glucuronide metabolites could not be detected in milk.

At high doses (45 mg/kg or more) and SDM plasma concentrations exceeding 20 μg/ml, a capacity limited metabolism of SDM to SCH₂OH was noticed, viz, asteady state concentration of SCH₂OH and a biphasic elimination pattern for SDM and SCH,OH in plasma and milk.

The mean ultrafiltrate ratios of the milk to plasma concentrations with respect to SDM, SCH₂OH, SOH, and N₄‐SDM were: 0.69, 0.22, 020, and 0.63, respectively.

The total amount of SDM and its metabolites recovered from the milk after milking twice daily over the whole experimental time was less than 2% of the applied dose.

A bioassay method allowed of detecting qualitatively SDM concentrations exceeding 0.2 μg/ml in plasma or milk. Withholding times for edible tissues and milk are suggested.     

Pharmacokinetics, metabolism and renal clearance of sulphatroxazole in calves and cows

The pharmacokinetic analysis of plasma concentration--time curves after a single i.v. dose of 20 mg/kg sulphatroxazole (STZ) to calves and cows revealed a small distribution volume of STZ (mean VD(area) = 0.22-0.26 l/kg) and an age dependent elimination (mean t1/2 6.6-18.8 h). In calves and cows, STZ was extensively metabolized into the N4-acetyl and 5-hydroxy derivatives. In the plasma of calves, the N4-acetyl metabolite (N4-STZ) was present in greater amounts than the hydroxy metabolite (5-OH-STZ), while in cows' plasma concentration of these two metabolites were similar. In the milk of dairy cows STZ concentrations paralleled those of the metabolites and were approximately 21 times lower than corresponding plasma concentrations. The mean plasma protein binding of STZ and its metabolites ranged from 36.4 to 82.5% of total concentration. The N4-STZ derivative was excreted by tubular secretion; the 5-OH-STZ and the parent compound, mainly by glomerular filtration. In calves the majority of STZ administered was excreted as N4-STZ (40-52%), while in cows the parent drug dominated the urinary excretion (36%).     

Residues of sulphadimidine and its metabolites in eggs following oral sulphadimidine medication of hens

The depletion of sulphadimidine (SDM) and its N4-acetyl and hydroxy metabolites was studied in eggs laid by hens after administration of either a single or multiple oral dosages of 100 mg SDM/kg. During medication and until 1 day after the last dose, the SDM and its metabolite concentrations in the egg white exceeded those in the egg yolk and reflected the plasma levels. In the period starting 2 days after the (last) dosage, the SDM concentration in the yolk became higher than in the egg white, and the drug depletion curves ran parallel. The mean maximum amount of SDM found in the whole egg was 1500 micrograms after a single and 1280 micrograms after multiple dosage. In eggs, traces of the N4-acetyl and 6-methylhydroxy metabolites could be detected (mainly in the egg white), and their concentrations were approximately 40 times lower than those of the parent drug. A highly significant correlation (P less than 0.005) was found between the development stage of the oocyte at the time of (last) medication and the amount of SDM found in the egg that developed from it. A period of 7 or 8 days after the (last) dosage of 100 mg SDM/kg/day is required to obtain SDM levels below 0.1 micrograms/g egg.     

Pharmacokinetics, bioavailability, and in vitro antibacterial activity of rifampin in the horse

The pharmacokinetics and bioavailability of rifampin were determined after IV (10 mg/kg of body weight) and intragastric (20 mg/kg of body weight) administration to 6 healthy, adult horses. After IV administration, the disposition kinetics of rifampin were best described by a 2-compartment open model. A rapid distribution phase was followed by a slower elimination phase, with a half-life (t1/2[beta]) of 7.27 +/- 1.11 hours. The mean body clearance was 1.49 +/- 0.41 ml/min.kg, and the mean volume of distribution was 932 +/- 292 ml/kg, indicating that rifampin was widely distributed in the body. After intragastric administration of rifampin in aqueous suspension, a brief lag period (0.31 +/- 0.09 hour) was followed by rapid, but incomplete, absorption (t1/2[a] = 0.51 +/- 0.32 hour) and slow elimination (t1/2[d] = 11.50 +/- 1.55 hours). The mean bioavailability (fractional absorption) of the administered dose during the first 24 hours was 53.94 +/- 18.90%, and we estimated that 70.0 +/- 23.6% of the drug would eventually be absorbed. The mean peak plasma rifampin concentration was 13.25 +/- 2.70 micrograms/ml at 2.5 +/- 1.6 hours after dosing. All 6 horses had plasma rifampin concentrations greater than 2 micrograms/ml by 45 minutes after dosing; concentrations greater than 3 micrograms/ml persisted for at least 24 hours. Mean plasma rifampin concentrations at 12 and 24 hours after dosing were 6.86 +/- 1.69 micrograms/ml and 3.83 +/- 0.87 micrograms/ml, respectively. We tested 162 isolates of 16 bacterial species cultured from clinically ill horses for susceptibility to rifampin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oxytetracycline pharmacokinetics, tissue depletion, and toxicity after administration of a long-acting preparation at double the label dosage

Oxytetracycline (OTC) concentration in plasma and tissues, plasma pharmacokinetics, depletion from tissue, and toxicity were studied in 30 healthy calves after IM administration of a long-acting OTC preparation (40 mg/kg of body weight) at double the label dosage (20 mg/kg). Plasma OTC concentration increased rapidly after drug administration, and by 2 hours, mean (+/- SD) values were 7.4 +/- 2.6 micrograms/ml, Peak plasma OTC concentration was 9.6 +/- 2.6 micrograms/ml, and the time to peak plasma concentration was 7.6 +/- 4.0 hours. Plasma OTC concentration decreased slowly for 168 hours (elimination phase) after drug administration, and the elimination half-life was 23.9 hours. Plasma OTC concentration exceeded 3.8 micrograms/ml at 48 hours after drug administration. From 168 to 240 hours after drug administration, plasma OTC concentration decreased at a slower rate than that seen during the elimination phase. This slower phase was termed the depletion phase, and the depletion half-life was 280.7 hours. Tissue OTC concentration was highest in kidneys and liver. Lung OTC concentration exceeded 4.4 micrograms/g of tissue and 2.0 micrograms/g of tissue at 12 and 48 hours after drug administration, respectively. The drug persisted the longest in kidneys and liver. At 42 days after drug administration, 0.1 micrograms of OTC/g of kidney was detected. At 49 days after drug administration, all OTC tissue concentrations were below the detectable limit. Reactions and toxicosis after drug administration were limited to an anaphylaxis-like reaction (n = 1) and injection site swellings (n = 2).     

Comparative pharmacokinetics, bioavailability and renal clearance of five parenteral oxytetracycline-20% formulations in dairy cows

Oxytetracycline (OTC) concentrations on plasma and milk of dairy cows were determined following a single intramuscular injection of five oxytetracycline-20% formulations at a dosage of approximately 10 mg/kg. For obtaining pharmacokinetic reference parameters, one 10% OTC formulation was administered intravenously. The five 20% formulations were compared and evaluated pharmacokinetically with respect to absorption rate, peak plasma and milk OTC concentrations, biological half-life, and relative bioavailability. The mean maximum plasma OTC concentrations varied between 4.5 and 6.8 micrograms/ml and were achieved between 5 and 10 h p.i., depending on the formulation involved. The mean maximum milk concentrations, ranging from 1.12 to 1.92 micrograms/ml, were achieved 12 to 24 h p.i. A plasma OTC concentration exceeding 0.5 microgram/ml was maintained for 48 h to 70 h, and in milk for 33 to 49 h, depending on the formulation involved. Formulations exhibiting the lowest clinically noticeable irritation showed the highest peak plasma OTC concentrations and the best bioavailability. Among the formulations the calculated withholding periods for milk were in the range of 3 to 4 days and for edible tissues of 9 to 14 days. The OTC and creatinine clearances were significantly correlated to each other and to the urinary flow. OTC was excreted predominantly by glomerular filtration, partly by tubular secretion minus urogenital (distal renal tubuli and bladder) reabsorption.     

Intramuscular and oral disposition of enrofloxacin in African grey parrots following single and multiple doses

The intramuscular (IM) and oral (PO) disposition of enrofloxacin, a new fluoroquinolone antimicrobial drug, were evaluated in African grey parrots. Peak enrofloxacin concentration, mean (+/- SEM), at 1 h following a 15-mg/kg IM dose was 3.87 (+/- 0.27) micrograms/ml and declined with a mean residence time of 3.05 h. Peak enrofloxacin plasma concentrations at 2 to 4 h following oral doses of 3, 15, and 30 mg/kg were 0.31 (+/- 0.11), 1.12 (+/- 0.11), and 1.69 (+/- 0.23) micrograms/ml, respectively, and declined with a mean residence time of 3.44-5.28 h. The relative bioavailability of the 15-mg/kg oral dose was 48%. An equipotent metabolite, ciprofloxacin, was detected in plasma at concentrations ranging from 3 to 78% of those of enrofloxacin. Enrofloxacin concentrations and area under the curve were significantly lower, the mean residence time significantly shorter and the ciprofloxacin/enrofloxacin ratios higher, following 10 days of oral treatment at 30 mg/kg every 12 h. Following 10 days of treatment, no significant biochemical changes were noted; however, polydipsia and polyuria occurred in treated birds, but resolved quickly upon discontinuation of enrofloxacin administration. These studies indicate that a rational starting dose for enrofloxacin in psittacines (7.5-30 mg/kg BID) should be higher than those in other domestic animals.     

Pharmacokinetics of cefotaxime in the domestic cat

Cefotaxime was administered as single IV or IM dose for the purpose of examining its pharmacokinetics in healthy cats. The mean predicted plasma concentration of cefotaxime in 6 cats at 0 time after a single IV dosage of 10 mg/kg of body weight was 88.9 micrograms/ml. The mean plasma concentrations decreased to 10.8 micrograms/ml at 2 hours, 3.7 micrograms/ml at 3 hours, and 0.5 microgram/ml at 6 hours. The half-life was 0.98 +/- 0.25 hour (mean +/- SD), and the total body clearance was determined to be 2.76 +/- 1.25 ml/min/kg. After a single IM injection of 10 mg/kg of body weight, the mean maximum observed plasma concentration was 36.2 micrograms/ml at 0.75 hour. The mean absorption half-life was 0.24 hour. In 2 animals, the bioavailability of an IM injection was 98.2% and 93.0%.     

Effect of probenecid on disposition kinetics of ampicillin in horses.

The effect of an oral dose of probenecid on the disposition kinetics of ampicillin was determined in four horses. An intravenous bolus dose (10 mg/kg) of ampicillin sodium was administered to the horses on two occasions. On the first occasion the antibiotic was administered on its own, and on the second occasion it was administered one hour after an oral dose of 75 mg/kg probenecid. The plasma concentration of probenecid reached a mean (+/- se) maximum concentration (Cmax) of 188-6 +/- 19.3 micrograms/ml after 120.0 +/- 21.2 minutes and concentrations greater than 15 micrograms/ml were present 25 hours after it was administered. The disposition kinetics of ampicillin were altered by the presence of probenecid and as a result the antibiotic had a slower body clearance (ClB; 109.4 +/- 6.71 ml/kg hours compared with 208.9 +/- 26.2 ml/kg hours) a longer elimination half-life (t1/2 beta 1.198 hours compared with 0.701 hours) and consequently a larger area under the plasma concentration versus time curve (AUC 92.3 +/- 5.09 mg/ml hours compared with 35.95 +/- 3.45 mg/ml hours) when compared with animals to which ampicillin was administered alone. The ampicillin concentrations observed suggest that the dosing interval for horses may be increased from between six and eight hours to 12 hours when probenecid is administered in conjunction with the ampicillin.     

Pharmacokinetics and therapeutic efficacy of rimantadine in horses experimentally infected with influenza virus A2.

OBJECTIVE: To determine pharmacokinetics of single and multiple doses of rimantadine hydrochloride in horses and to evaluate prophylactic efficacy of rimantadine in influenza virus-infected horses. ANIMALS: 5 clinically normal horses and 8 horses seronegative to influenza A. PROCEDURE: Horses were given rimantadine (7 mg/kg of body weight, i.v., once; 15 mg/kg, p.o., once; 30 mg/kg, p.o., once; and 30 mg/kg, p.o., q 12 h for 4 days) to determine disposition kinetics. Efficacy in induced infections was determined in horses seronegative to influenza virus A2. Rimantadine was administered (30 mg/kg, p.o., q 12 h for 7 days) beginning 12 hours before challenge-exposure to the virus. RESULTS: Estimated mean peak plasma concentration of rimantadine after i.v. administration was 2.0 micrograms/ml, volume of distribution (mean +/- SD) at steady-state (Vdss) was 7.1 +/- 1.7 L/kg, plasma clearance after i.v. administration was 51 +/- 7 ml/min/kg, and beta-phase half-life was 2.0 +/- 0.4 hours. Oral administration of 15 mg of rimantadine/kg yielded peak plasma concentrations of < 50 ng/ml after 3 hours; a single oral administration of 30 mg/kg yielded mean peak plasma concentrations of 500 ng/ml with mean bioavailability (F) of 25%, beta-phase half-life of 2.2 +/- 0.3 hours, and clearance of 340 +/- 255 ml/min/kg. Multiple doses of rimantadine provided steady-state concentrations in plasma with peak and trough concentrations (mean +/- SEM) of 811 +/- 97 and 161 +/- 12 ng/ml, respectively. Rimantadine used prophylactically for induced influenza virus A2 infection was associated with significant decreases in rectal temperature and lung sounds. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of rimantadine to horses can safely ameliorate clinical signs of influenza virus infection.     

Disposition of tylosin in goats

The disposition kinetics of tylosin was studied in goats after intravenous (i.v.) or intramuscular (i.m.) injection of 15 mg/kg body wt. Following i.v. injection, tylosin was rapidly and widely distributed with a distribution half-life of 0.2 h and volume of distribution of 1.7 l/kg. It was slowly eliminated with a mean elimination half-life of 3.04 h and a total body clearance rate of 6.8 ml/kg/min. Following i.m. injection, tylosin was slowly absorbed (tau 1/2 ab of 1.82 h). Tylosin concentration in serum was greater than 1 microgram/ml after 1 h and persisted up to 12 h post-injection. The peak concentration (Cmax 2.38 micrograms/ml) was obtained after 4.19 h. The systemic bioavailability of tylosin injected intramuscularly was 72.6% and the serum protein bound fraction was 37.59% of the total drug. Tylosin was excreted in milk and urine at concentrations much higher than that in serum. Low concentrations of tylosin were reported in ruminal juice of goats. In conclusion tylosin should be injected every 14 h to obtain an appreciable concentration in serum, milk and urine.     

Age and dosage dependency in the plasma disposition and the renal clearance of sulfamethazine and its N4-acetyl and hydroxy metabolites in calves and cows

Plasma disposition, protein binding, urinary recovery, and renal clearance of sulfamethazine (SMZ), its N4-acetylsulfamethazine (N4-SMZ), and its 2 hydroxy metabolites--6-hydroxymethylsulfamethazine (SCH2OH) and 5-hydroxysulfamethazine (SOL)--and the glucuronide of the latter were studied in 7 cows and 7 calves to determine the relationship between these values and the age of the animal and dosage applied. A capacity-limited hydroxylation of SMZ into SCH2OH was observed in cows and calves given dosages of 100 to 200 mg/kg. A biphasic SMZ elimination curve and steady state in SCH2OH plasma concentration (6 to 15 micrograms/ml) were observed. The N4-SMZ plasma concentration-time curve was parallel to that of SMZ at the dosages and in all animals. The total body clearance and the cumulative urinary recovery (expressed as percentage of the dose) for SMZ and its metabolites depended on drug dosage and age of the animals. At dosages of SMZ less than 25 mg/kg, the main metabolite in the urine of calves and cows was SCH2OH (23% to 55.2%), whereas in calves given a larger dosage (100 mg/kg), the N4-SMZ and SOH percentages increased. The plasma protein binding of SMZ and its metabolites depended on the SMZ plasma concentration. Hydroxylation lowered the protein binding (from 75-80%) to 50%. The renal clearance of SMZ was dependent on urine flow in all animals. The renal clearance of the SCH2OH metabolite was 2 to 3 times greater than the creatinine clearance value; thus, this compound was excreted by glomerular filtration and partly by tubular secretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ormetoprim-sulfadimethoxine in cattle: pharmacokinetics, bioavailability, distribution to the tears, and in vitro activity against Moraxella bovis

The pharmacokinetics, bioavailability, and distribution to the tears of ormetoprim (OMP; 5.5 mg/kg of body weight) and sulfadimethoxine (SDM; 27.5 mg/kg of body weight) were determined following IV or oral administration to 6 Holstein steers. After IV administration, the disposition kinetics of both drugs were best described by a 2-compartment open model. Sulfadimethoxine had a moderately rapid distribution phase, followed by a slower elimination phase, with a mean half-life (t 1/2) of 7.91 hours. The mean volume of distribution of SDM was 185 ml/kg, and the mean body clearance was 0.28 ml/min X kg. The concentration of SDM in tears was lower than the corresponding plasma concentration, and the elimination of SDM from tears (t 1/2 = 3.02 hours) was significantly faster than its elimination from plasma (t 1/2 = 7.91 hours). The disposition of OMP administered IV was characterized by a rapid distribution phase, followed by a rapid elimination phase (t 1/2 = 1.37 hours). The high values of the mean volume of distribution (1,450 ml/kg) and mean rate of body clearance (13.71 ml/min X kg) indicated that OMP was widely distributed in the body and was rapidly cleared from the body. Ormetoprim concentrations in tears exceeded corresponding plasma concentrations, and the elimination of OMP from tears was significantly slower (t 1/2 = 1.91 hours) than from plasma (t 1/2 = 1.37 hours). After oral administration of an OMP-SDM combination in bolus form, the absorption of SDM was slow (absorption t 1/2 = 3.32 hours), but complete.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma disposition and renal clearance of sulphadimidine and its metabolites in laying hens

Plasma disposition of sulphadimidine (SDM) and its metabolites was studied in laying hens after 100 mg SDM kg-1 doses were administered as a single intravenous dose, a single oral dose and multiple oral doses once daily for five consecutive days. SDM was extensively metabolised by acetylation and hydroxylation. In plasma, the metabolite observed with the highest concentration was N4-acetylsulphadimidine (N4-SDM) followed by hydroxymethylsulphadimidine (CH2OH) and 5-hydroxysulphadimidine. Following intravenous administration a biphasic elimination (as seen for a capacity limited reaction) pattern for SDM and its metabolites was observed. Multiple (5x) SDM dosing revealed plasma SDM concentrations ranging between 7 and 108 micrograms ml-1; within 96 hours of termination of the multiple SDM dosing, the plasma SDM concentration was below 0.01 micrograms ml-1. The renal clearances of N4-SDM and the hydroxy metabolites were approximately 10 times greater than that of SDM. The SDM mass balance (faecal/urinary recovery) showed a loss of 56 per cent after intravenous dosage and of 67 per cent after a single oral dosage; the hydroxy metabolites accounted for the highest percentage in faeces/urine. Thus additional metabolic pathways must exist in laying hens.     

Pharmacokinetics and milk residues of butorphanol in dairy cows after single intravenous administration

The pharmacokinetics of butorphanol tartrate were investigated following intravenous administration of 0.25 mg/kg of body weight to six healthy non-lactating Jersey cows. Three lactating Holstein cows also received 0.045 mg of butorphanol/kg of body weight intravenously to determine the extent and duration of drug transfer into milk. A radioimmunoassay technique was used to measure butorphanol concentrations in plasma and milk. The disposition of butorphanol following intravenous administration was characterized by rapid and extensive distribution followed by a slower elimination phase. Apparent volume of distribution was 4.178 ± 1.145 (mean ± SD) I/kg, mean elimination half-life was 82 min, and clearance was 34.6 ± 7.7 ml/min/kg. Trace quantities of butorphanol were detected in the cow's milk for up to 36 h following administration. These pharmacokinetic data were compared with pharmaco-kinetic and pharmacodynamic data for butorphanol in other species and for three other potent opioids in related ruminant species.     

Pharmacokinetics of phenylbutazone in mature Holstein bulls: steady-state kinetics after multiple oral dosing

Six mature Holstein bulls were given an 8-day course of phenylbutazone (PBZ) orally (loading dose, 12 mg of PBZ/kg of body weight and 7 maintenance doses of 6 mg of PBZ/kg, q 24 h). Plasma concentration-vs-time data were analyzed, using nonlinear regression modeling. The harmonic mean +/- pseudo-SD of the biologic half-life of PBZ was 61.8 +/- 12.8 hours. The arithmetic mean +/- SEM of the total body clearance and apparent volume of distribution were 0.0021 +/- 0.0001 L/h/kg and 0.201 +/- 0.009 L/kg, respectively. The predicted mean minimal plasma concentration of PBZ with this dosage regimen was 75.06 +/- 4.05 micrograms/ml. The predicted minimal plasma drug concentration was compared with the observed minimal plasma drug concentration in another group of bulls treated with PBZ for at least 60 days. Sixteen mature Holstein bulls were given approximately 6 mg of PBZ/kg, PO, daily for various musculoskeletal disorders. The mean observed minimal plasma concentration of PBZ in the 16 bulls was 76.10 +/- 2.04 micrograms/ml, whereas the mean predicted minimal plasma concentration was 74.69 +/- 3.10 micrograms/ml. Dosages of 4 to 6 mg of PBZ/kg, q 24 h, or 10 to 14 mg of PBZ/kg, q 48 h, provided therapeutic plasma concentrations of PBZ with minimal steady-state concentrations between 50 and 70 micrograms/ml.