Pharmacokinetics of penicillin G procaine versus penicillin G potassium and procaine hydrochloride in horses

OBJECTIVE: To compare the pharmacokinetics of penicillin G and procaine in racehorses following i.m. administration of penicillin G procaine (PGP) with pharmacokinetics following i.m. administration of penicillin G potassium and procaine hydrochloride (PH). ANIMALS: 6 healthy adult mares. PROCEDURE: Horses were treated with PGP (22,000 units of penicillin G/kg of body weight, i.m.) and with penicillin G potassium (22,000 U/kg, i.m.) and PH (1.55 mg/kg, i.m.). A minimum of 3 weeks was allowed to elapse between drug treatments. Plasma and urine penicillin G and procaine concentrations were measured by use of high-pressure liquid chromatography. RESULTS: Median elimination phase half-lives of penicillin G were 24.7 and 12.9 hours, respectively, after administration of PGP and penicillin G potassium. Plasma penicillin G concentration 24 hours after administration of penicillin G potassium and PH was not significantly different from concentration 24 hours after administration of PGP. Median elimination phase half-life of procaine following administration of PGP (15.6 hours) was significantly longer than value obtained after administration of penicillin G potassium and PH (1 hour). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that i.m. administration of penicillin G potassium will result in plasma penicillin G concentrations for 24 hours after drug administration comparable to those obtained with administration of PGP Clearance of procaine from plasma following administration of penicillin G potassium and PH was rapid, compared with clearance following administration of PGP.     

Adverse reaction to procaine penicillin G in horses

Adverse reactions to intramuscular injections of procaine penicillin G are reported in 11 horses, five of which died. The clinical findings are presented and suggest central nervous involvement in most cases. Post mortem findings in one horse were consistent with anaphylaxis whereas in other cases the clinical findings, duration of treatment, speed of onset and subsequent completion of treatment supports diagnosis of an acute procaine toxicity syndrome.     

The role of procaine in adverse reactions to procaine penicillin in horses

Procaine penicillin is a commonly used antibiotic in equine medicine but its use is associated with a substantial incidence of adverse reactions. Soluble procaine concentrations were determined by HPLC in several commercially available procaine penicillin preparations, including some that were involved in adverse reactions. The mean (+/- SEM) soluble procaine concentrations in the veterinary preparations was 20.18 +/- 5.07 mg/ml, which was higher than the concentration in the only procaine penicillin preparation for use in humans in Australia of 7.3 mg/ml. Heating the veterinary procaine penicillin preparations to 50 degrees C for 1 day led to a significant (P less than 0.01) increase in the amount of soluble procaine. Heating to 50 degrees C for 7 days also produced a significant (P less than 0.02) increase. Soluble procaine tended to return to baseline concentrations when veterinary procaine penicillin preparations were heated to 50 degrees C for 2 days then stored for 7 days at room temperature. Administration of procaine HCl intravenously (IV) at 2, 5, and 10 mg/kg produced behavioural, locomotor and vascular reactions, which were clinically similar to those reported in adverse reactions to procaine penicillin. The more severe reactions occurred at higher doses, although different horses responded variably at the same dose. Some adverse reactions lead to recumbency but none were fatal. The blood procaine concentrations 1 min after IV administration averaged 19.0 +/- 12.6 and 25.3 +/- 16 micrograms/ml at 2.5 mg/kg and 5 mg/kg, respectively. Ten min after administration, blood procaine concentrations were significantly higher (P less than 0.001) in the 5 mg/kg group than in the 2.5 mg/kg group. Intramuscular (IM) procaine HCl at 5 mg/kg produced significantly lower (P less than 0.001) blood concentrations than similar IV doses, and, in contrast to the IV doses, the amount of procaine in the blood was significantly higher 5 and 10 min after administration than it was after 1 min. Mild excitatory reactions in 4/5 horses were noted 5 to 10 min after IM administration. Administration of diazepam 20 s before procaine HCl prevented the excitatory adverse reaction in 2/2 horses, but administration after the procaine did not influence the outcome.     

Antibiotic residues in milk following bulbar subconjunctival injection of procaine penicillin G in dairy cows

OBJECTIVE: To determine whether, and at what time, penicillin enters milk at a concentration that is detectable following bulbar subconjunctival injection in lactating dairy cows. DESIGN: Randomized clinical trial. ANIMALS: 66 Holstein cows that were at least 2 weeks past calving and had not been treated with antibiotics in the preceding 30 days. PROCEDURE: Cows were randomly assigned to receive a treatment of 1 ml (300,000 units) procaine penicillin G by bulbar subconjunctival injection or remain untreated. Composite milk samples were collected immediately before treatment and 4, 10, 16, 22, 28, and 40 hours after treatment. Milk samples were tested by use of a commercial test for beta-lactam antibiotics. RESULTS: Among penicillin-treated cows, the first positive test results were observed 4 hours after treatment, and the last positive result was observed 22 hours after treatment. The percentages of positive test results before treatment and at 4, 10, 16, 22, 28, and 40 hours after treatment were 0, 9, 87, 42, 8, 0, and 0%, respectively. None of the untreated cows had positive test results for beta-lactam antibiotics at any sampling time. CONCLUSIONS AND CLINICAL RELEVANCE: Penicillin was detected in milk for up to 22 hours after a single subconjunctival injection of procaine penicillin G in cows. This result should be considered when recommending milk withholding periods following the administration of penicillin by this route in lactating dairy cows.     

A study of the disposition of procaine penicillin G in feedlot steers following intramuscular and subcutaneous injection

The disposition of an aqueous suspension of procaine penicillin G (300 000 U/ mL) was studied in feedlot steers. Four groups of three steers were used. Steers in groups 1 and 2 received procaine penicillin G once daily for 5 days intramuscularly (i.m.) at a dose of 24 000 U/kg (group 1) or of 66 000 U/kg (group 2). The injection on the last day was administered in the gluteal muscle. Steers in group 3 (i.m. neck injection) and group 4 [subcutaneous (s.c.) injection] each received a single dose of procaine penicillin G at a dose of 66 000 U/kg. From every animal, after the last injection in groups 1 and 2 and following the single injection in groups 3 and 4, a series of blood samples was taken at fixed time intervals. The plasma from these samples was analysed for penicillin G by a high performance liquid chromatography (HPLC) assay in order to determine the disposition of penicillin. The maximum plasma concentration (C_max) and the area under the curve (AUC) were significantly different between groups 1 and 2, but we found no difference in the disappearance rate constant between these two groups. Group 4 single s.c. injections produced a lower mean C_max (1.85 ± 0.27 ng/mL) than the mean C_max (4.24 ± 1.08 μg/mL) produced in group 3 by i.m. injections into the neck muscle or the mean C_max (2.63 ± 0.27 μg/mL) produced in group 2 by i.m. injections into the gluteal muscle. However the mean C_max produced by i.m. injections into the neck muscles (group 3) was higher than the mean C_max produced by i.m. injections into the gluteal muscle (group 2). Additionally, the disappearance t_½, was longer (18.08 h) in group 4 following the s.c. injection and shorter (8.85 h) in group 3 following the i.m. neck injection, than the t_½ following administration of the same dose i.m. into the gluteal muscle (15.96 h) in group 2. In this study, when procaine penicillin G was injected into the gluteal muscle, doses of 66 000 U/kg were necessary to produce plasma concentrations that were above a minimum inhibitory concentration (MIC) for penicillin G of 1.0 μg/mL as compared to doses of 24 000 U/kg.     

Effect of Tomanol on the pharmacokinetics and tissue distribution of penicillin G in dairy cows

Following concomitant intravenous administration of Tomanol and sodium penicillin G to six Dutch Friesian dairy cows a significant decrease in total body clearance of penicillin (34.7%) and a prolongation of the elimination half-life of penicillin (17.2%) was observed. Tomanol did not affect other pharmacokinetic parameters such as rate constants of drug transfer (k12/k21, alpha en beta), distribution volume of the central compartment (V1), and extrapolated serum drug levels. Intravenous or intramuscular administration of Tomanol had no effect on the tissue distribution of penicillin G, because neither a change in the ratios of muscle to serum and of kidney cortex to serum nor a change in an induced steady state level of low penicilline G serum concentrations was observed. From the data obtained it is concluded that concomitant Tomanol administration with penicillin induces an elevation of the serum penicillin concentration and prolongs the persistence of penicillin residues in carcass meat and organs.     

Comparison of post-operative inflammatory response in horses undergoing elective castration treated preoperatively with ceftiofur crystalline free acid or procaine penicillin G

Castration is among the most common surgical procedures performed in the horse (Equus Caballus) and a variety of post-operative complications can occur. This study aims to determine if a single dose of long-acting ceftiofur crystalline free acid (CCFA) used as a preoperative antimicrobial in equine field castrations offers any reduction in post-operative inflammatory markers when compared to procaine penicillin G (PPG). Sixty-five horses aged 8 months to 2 years were randomly assigned to the CCFA (n = 33) or PPG (n = 32) treatment groups. Horses were castrated under general anaesthesia using a closed castration technique with removal of the median raphe. Quantitative and qualitative inflammatory markers were measured and short-term complications were recorded post-operatively on Days 3, 8 and 14. No clinically significant difference in any post-operative inflammatory markers between the CCFA and PPG group was detected. In the CCFA group, 48% of horses experienced short-term post-operative complications compared to 31% in the PPG group. Regardless of the preoperative treatment, castration induced significant elevation in serum amyloid A (P<0.0001), preputial oedema (P<0.0001) and scrotal oedema (P<0.0001) at Day 3. These values returned to baseline levels by Day 8. Horses with grade 3 or above preputial oedema had elevated serum amyloid A values (P<0.001). The data from this study indicate CCFA used as a preoperative antibiotic for routine castration offers no advantages over PPG. The difference in complication rate between groups is likely of minimal clinical importance, as all complications were mild and self-limiting.     

Efficacy of intramammary treatment with procaine penicillin G vs. procaine penicillin G plus neomycin in bovine clinical mastitis caused by penicillin-susceptible,gram-positive bacteria--a double blind field study

The efficacy of intramammary treatments containing procaine penicillin G alone (treatment A) or a combination of procaine penicillin G and neomycin (treatment B) was compared in treating clinical bovine mastitis caused by gram-positive bacteria susceptible in vitro to penicillin G. Both treatments were supplemented with a single intramuscular injection of procaine penicillin G on the first day of treatment. The study was carried out using a double blind design on commercial dairy farms in Southern Finland. A total of 56 quarters were treated with treatment A and 61 with treatment B. The cure rates for both treatments were equal, which suggests that the use of the penicillin G-aminoglycoside combination does not increase the efficacy of the treatment over that achieved by using penicillin G alone in bovine clinical mastitis caused by penicillin-susceptible, gram-positive bacteria.     

Kinetics and residues after intraperitoneal procaine penicillin G administration in lactating dairy cows

This paper describes the pharmacokinetic profile of procaine penicillin G after intraperitoneal (IP) administration in eight lactating dairy cows. Procaine pencillin G (PPG, 21 000 IU/kg) was deposited into the abdominal cavity of each cow following an incision in the right paralumbar fossa. Blood and milk samples were taken over the following 10 days, at which point the cows were euthanized. Plasma, milk, muscle, liver, and kidney penicillin concentrations were determined by HPLC, with a limit of quantification of 5 ng/mL for plasma and milk and 40 ng/g for tissue samples. A noncompartmental method was used to analyze plasma kinetics. The mean pharmacokinetic parameters (±SD) were: C _max, 5.5 ± 2.6 μg/mL; T _max, 0.75 ± 0.27 h; AUC _0-∞, 10.8 ± 4.9 μg·h/mL; MRT , 2.2 ± 0.9 h. All milk from treated cows contained detectable penicillin residues for a minimum of three milkings (31 h) and maximum of five milkings (52 h) after administration. Concentrations of penicillin in all muscle, liver, and kidney samples taken 10 days postadministration were below the limit of quantification. Necropsy examinations revealed foci of hemorrhage on the rumenal omentum of most cows but peritonitis was not observed. Systemic inflammation as determined by change in leukogram or plasma fibrinogen was noted in one cow. The results of this study demonstrate that IP PPG is absorbed and eliminated rapidly in lactating dairy cows.     

Comparison of the pharmacokinetics of penicillin G and ampicillin in the horse.

The affinity and the binding capacity of horse serum proteins for ampicillin and penicillin G were measured by equilibrium dialysis or ultrafiltration technique. From the figures thus obtained it may be concluded that in the range of therapeutic concentrations the protein-bound fraction accounts for 6 X 8-8 per cent of the total ampicillin concentration and for 52-54 per cent of the total penicillin G concentration in serum. The rate of elimination of ampicillin and penicillin G in horses was assessed by following serum concentrations after a single intravenous injection. The biological half life of ampicillin was found to be 93 min and that of penicillin G 53 min in adult horses with unimpaired circulation and intact kidney and liver function.     

Effects of experimentally induced Streptococcus suis infection on the pharmacokinetics of penicillin G in pigs

The pharmacokinetics of potassium penicillin G were studied in both healthy (n = 8) and experimentally Streptococcus-suis-infected (n = 6) pigs following intramuscular administration (15,000 iu/kg). Streptococcus-suis infection was induced artificially in young cross-bred pigs by subcutaneous inoculation with 9 x 10(8) to 10(9) colony-forming units of S. suis. The rectal temperature of infected pigs was significantly increased (P less than 0.01) before penicillin G injection and this was maintained for 8 h after the drug was given. Other clinical symptoms were also present. The serum concentration-time data for penicillin were found to fit a one-compartment open model with first-order absorption in the two groups of pigs. Significant changes were not observed between healthy and diseased pigs in following parameters: A, Ka, Ke and Tmax. However, in diseased pigs, significant increases (P less than 0.01) were found in Vd and ClB, and significant decreases (P less than 0.01) in Cmax and AUC occurred. The increased body clearance (ClB) and greater apparent volume of distribution (Vd) of penicillin G could partly explain why the serum values of the drug were much lower in diseased pigs than in healthy pigs.     

Effect of body weight on the pharmacokinetics of flunixin meglumine in miniature horses and quarter horses

In most species, large variations in body size necessitate dose adjustments based on an allometric function of body weight. Despite the substantial disparity in body size between miniature horses and light‐breed horses, there are no studies investigating appropriate dosing of any veterinary drug in miniature horses. The purpose of this study was to determine whether miniature horses should receive a different dosage of flunixin meglumine than that used typically in light‐breed horses. A standard dose of flunixin meglumine was administered intravenously to eight horses of each breed, and three‐compartmental analysis was used to compare pharmacokinetic parameters between breed groups. The total body clearance of flunixin was 0.97 ± 0.30 mL/min/kg in miniature horses and 1.04 ± 0.27 mL/min/kg in quarter horses. There were no significant differences between miniature horses and quarter horses in total body clearance, the terminal elimination rate, area under the plasma concentration versus time curve, apparent volume of distribution at steady‐state or the volume of the central compartment for flunixin (P > 0.05). Therefore, flunixin meglumine may be administered to miniature horses at the same dosage as is used in light‐breed horses.     

Effect of feeding on the pharmacokinetics of oral minocycline in healthy adult horses

Minocycline is commonly used to treat bacterial and rickettsial infections in adult horses but limited information exists regarding the impact of feeding on its oral bioavailability. This study's objective was to compare the pharmacokinetics of minocycline after administration of a single oral dose in horses with feed withheld and with feed provided at the time of drug administration. Six healthy adult horses were administered intravenous (2.2 mg/kg) and oral minocycline (4 mg/kg) with access to hay at the time of oral drug administration (fed) and with access to hay delayed for 2 hr after oral drug administration (fasted), with a 7‐day washout between treatments. Plasma concentration versus time data was analyzed based on noncompartmental pharmacokinetics. Mean ± SD bioavailability (fasted: 38.6% ± 4.6; fed: 15.7% ± 2.3) and C_max (fasted: 1.343 ± 0.418 μg/ml; fed: 0.281 ± 0.157 μg/ml) were greater in fasted horses compared to fed horses (p < .05 both). Median (range) T_max (hr) in fasted horses was 2.0 (1.5–3.5) and in fed horses was 5.0 (1.0–8.0) and was not significantly different between groups. Overnight fasting and delaying feeding hay 2 hr after oral minocycline administration improve drug bioavailability and thus plasma concentrations.     

Intravenous and sublingual buprenorphine in horses: pharmacokinetics and influence of sampling site

ObjectiveTo describe the pharmacokinetics and adverse effects of intravenous (IV) and sublingual (SL) buprenorphine in horses, and to determine the effect of sampling site on plasma concentrations after SL administration.Study designRandomized crossover experiment; prospective study.AnimalsEleven healthy adult horses between 6 and 20 years of age and weighing 487–592 kg.MethodsIn the first phase; buprenorphine was administered as a single IV or SL dose (0.006 mg kg^?1) and pharmacokinetic parameters were determined for each route of administration using a noncompartmental model. In the second phase; the jugular and lateral thoracic veins were catheterized for simultaneous venous blood sampling, following a dose of 0.006 mg kg^?1 SL buprenorphine. For both phases, plasma buprenorphine concentrations were measured using ultra-performance liquid chromatography with mass spectrometry. At each sampling period, horses were assessed for behavioral excitement and gastrointestinal motility.ResultsFollowing IV administration, buprenorphine mean ± SD half-life was 5.79 ± 1.09 hours. Systemic clearance (Cl) following IV administration was 6.13 ± 0.86 mL kg^?1 minute^?1 and volume of distribution at steady-state was 3.16 ± 0.65 L kg^?1. Following IV administration, horses showed signs of excitement. Gastrointestinal sounds were decreased following both routes of administration; however, none of the horses exhibited signs of colic. There was a significant discrepancy between plasma buprenorphine concentrations measured in the jugular vein versus the lateral thoracic vein following phase 2, thus pharmacokinetic parameters following SL buprenorphine are not reported.Conclusions and clinical relevanceBuprenorphine has a long plasma half-life and results in plasma concentrations that are consistent with analgesia in other species for up to 4 hours following IV administration of this dose in horses. While buprenorphine is absorbed into the circulation following SL administration, jugular venous sampling gave a false measurement of the quantity absorbed and should not be used to study the uptake from SL administration.