The effect of food or water deprivation on paracetamol pharmacokinetics in calves

This study investigated the effect of food or water deprivation on the pharmacokinetics of paracetamol in 30 Holstein-Friesian preruminant calves (10 controls, 10 food withheld and 10 water-deprived) aged 24-25 days. Control calves were given paracetamol at 24-25 days and again at 28-29 days of age. In the food withheld and water-deprived calves paracetamol studies were performed before and after 4 days of food or water deprivation. In the control group there were no significant differences in pharmacokinetic parameters for paracetamol in 24-25 and 28-29-day-old calves. Witholding food for 4 days was associated with an increase in the mean residence time (MRT) of paracetamol (P < 0.01). When food was withheld total body clearance (ClB) of paracetamol was significantly decreased (P < 0.05). The volume of distribution (Vss) was not significantly altered. Similarly, water deprivation was associated with a significant increase in MRT and significant decrease in ClB of paracetamol (P < 0.01). The Vss was not significantly altered. Food or water deprivation also influenced the formation of major metabolites (glucuronide and sulphate) of paracetamol. It is concluded that food or water deprivation may impair the elimination drugs that undergo metabolism by UDP-glucuronyltransferase and sulphotransferase in cattle.     

The effect of short-term starvation or water deprivation on caffeine pharmacokinetics in calves

The aim of this study was to determine the effect of short-term starvation or water deprivation on the pharmacokinetics of caffeine in calves. The experiment was carried out on 30 Holstein-Friesian calves (10 calves in a control group, 10 calves in a 'starved' group and 10 calves in a 'water-deprived' group) aged 24-25 days. Control group calves were given caffeine at 24-25 and 28-29 days of age. In the experimental groups caffeine studies were performed before and after 4 days of starvation or water deprivation.In the control group no significant differences between the pharmacokinetic parameters of caffeine in 24-25 and 28-29 day-old calves were observed. Starvation for 4 days was associated with an increase in the mean residence time (MRT) of caffeine in each subject. The increase was statistically significant (P < 0.01). After starvation the total plasma clearance of caffeine decreased (about 20 per cent). The decrease was statistically significant (P < 0.05). The volume of caffeine distribution (V(ss)) was slightly but not significantly increased. Similarly, water deprivation was associated with significant increase in the mean residence time of caffeine in each subject. The total plasma clearance of caffeine decreased (about 30 per cent). This decrease was statistically significant (P < 0.01). The volume of caffeine distribution was slightly but not significantly decreased.Results obtained in this study indicate that short-term (for 4 days) starvation or water deprivation leads to a general inhibition of hepatic P450 enzymatic system and may impair the elimination of drugs that undergo metabolism by these enzymes.     

Effect of food on the pharmacokinetics of oral cefuroxime axetil in dogs

Cefuroxime axetil pharmacokinetic profile was investigated in 12 Beagle dogs after single intravenous and oral administration of tablets or suspension at a dose of 20 mg/kg, under both fasting and fed conditions. A three-period, three-treatment crossover study (IV, PO under fasting and fed condition) was applied. Blood samples were withdrawn at predetermined times over a 12-hr period. Cefuroxime plasma concentrations were determined by HPLC. Data were analyzed by compartmental analysis. No statistically significant differences were observed between formulations and feeding conditions on PK parameters. Independently of the feeding condition, absorption of cefuroxime axetil after tablet administration was low and erratic. The drug has been quantified in plasma in 3 out of 6 and 5 out of 6 dogs in the fasted and fed groups. For this formulation, the bioavailability (F), peak plasma concentration (C_max), and area under the concentration–time curve (AUC) of cefuroxime axetil were significantly enhanced (p < .05) by the concomitant ingestion of food (32.97 ± 13.47–14.08 ± 7.79%, 6.30 ± 2.62–2.74 ± 0.66 µg/ml, and 15.75 ± 3.98–7.82 ± 2.76 µg.hr/ml for F, C_max, and AUC in fed and fasted dogs, respectively), while for cefuroxime axetil suspension, feeding conditions affected only the rate of absorption, as reflected by the significantly shorter absorption half-life (T_½(a)) and time to peak concentration (T_max) (0.55 ± 0.27–1.15 ± 0.19 hr and 1.21 ± 0.22–1.70 ± 0.30 for T_½(a) and T_max in fed and fasted dogs, respectively). For cefuroxime axetil tablets, T > MIC (≤1 µg/ml) was <2 hr in fasted and ≈4 hr in fed animals, and for cefuroxime axetil suspension, T > MIC (≤1 µg/ml) was ≈5 hr and for T >MIC (≤4 µg/ml) was ≈2.5 hr for fasted and fed dogs, respectively. Cefuroxime axetil as a suspension formulation seems to be a better option than tablets. However, its short permanence in plasma could reduce its clinical usefulness in dogs.     

Clinical pharmacokinetics of flumequine in calves

The minimal inhibitory concentration (MIC) of flumequine for 249 Salmonella, 126 Escherichia coli, and 22 Pasteurella multocida isolates recovered from clinical cases of neonatal calf diarrhoea, pneumonia and sudden death was less than or equal to 0.78 microgram/ml. The pharmacokinetics of flumequine in calves was investigated after intravenous (i.v.), intramuscular (i.m.) and oral administration. The two-compartment open model was used for the analysis of serum drug concentrations measured after rapid i.v. ('bolus') injection. The distribution half-life (t1/2 alpha) was 13 min, elimination half-life (t1/2 beta) was 2.25 h, the apparent area volume of distribution (Vd(area)), and the volume of distribution at steady state (Vd(ss)) were 1.48 and 1.43 l/kg, respectively. Flumequine was quickly and completely absorbed into the systemic circulation after i.m. administration of a soluble drug formulation; a mean peak serum drug concentration (Cmax) of 6.2 micrograms/ml was attained 30 min after treatment at 10 mg/kg and was similar to the concentration measured 30 min after an equal dose of the drug was injected i.v. On the other hand, the i.m. bioavailability of two injectable oily suspensions of the drug was 44%; both formulations failed to produce serum drug concentrations of potential clinical significance after administration at 20 mg/kg. The drug was rapidly absorbed after oral administration; the oral bioavailability ranged between 55.7% for the 5 mg/kg dose and 92.5% for the 20 mg/kg dose. Concomitant i.m. or oral administration of probenecid at 40 mg/kg did not change the Cmax of the flumequine but slightly decreased its elimination rate. Flumequine was 74.5% bound in serum. Kinetic data generated from single dose i.v., i.m. and oral drug administration were used to calculate practical dosage recommendations. Calculations showed that the soluble drug formulation should be administered i.m. at 25 mg/kg every 12 h, or alternatively at 50 mg/kg every 24 h. The drug should be administered orally at 30 and 60 mg/kg every 12 and 24 h, respectively. Very large, and in our opinion impractical, doses of flumequine formulated as oily suspension are required to produce serum drug concentrations of potential clinical value.     

Age-dependent pharmacokinetics of phenylbutazone in calves

The pharmacokinetics of phenylbutazone (PBZ) in relation to age was studied in calves. The drug was applied intravenously to calves (dose 22 mg/kg), which were divided, depending on age, into three groups. Heparinised blood samples were taken in defined intervals. The concentrations of phenylbutazone and two of its metabolites were determined in plasma by high performance liquid chromatography. The pharmacokinetic data derived from 1-month-old calves revealed a longer persistence (elimination half-lives twice as long, total body clearance 40-50% lower) of PBZ in the body than in the other two groups of calves aged 3-6 months. With respect to the long elimination half-lives (mean values 39-94 h), caution is needed in case of repeated doses (accumulation).     

Probenecid infusion in mares: effect on para-aminohippuric acid clearance

Para-aminohippuric acid (PAHA, 0.1 mg/min/kg of body weight) was infused IV into 2 mares, followed by concurrent IV infusion of PAHA and probenecid (0.075, 0.15, 0.25, or 0.35 mg of probenecid/min/kg). Probenecid infusion reduced the clearance of PAHA at serum probenecid concentrations greater than 55 micrograms/ml. At 12-hour intervals, probenecid (in 5 repeated doses - 50, 75, 100, or 200 mg/kg) was administered by gavage to 2 mares. Mean serum probenecid concentration was greater than 55 micrograms/ml for all dosages. At dosages less than 200 mg/kg, accumulation of probenecid in the serum was minimal from the 1st to the 5th dose. At a dosage of 200 mg/kg, probenecid accumulated in the serum from the 1st to the 5th dose. Intragastric administration of 5 doses of probenecid (75 mg/kg) at 12-hour intervals to 6 mares reduced the clearance of PAHA by 50%. Bioavailability of probenecid was 117 and 102% for 2 mares after a single intragastric dose, compared with a single IV dose.     

Pharmacodynamics and pharmacokinetics of phenylbutazone in calves

Phenylbutazone (PBZ) was administered to six calves intravenously (i.v.) and orally at a dose rate of 4.4 mg/kg in a three-period cross-over study incorporating a placebo treatment to establish its pharmacokinetic and pharmacodynamic properties. Extravascular distribution was determined by measuring penetration into tissue chamber fluid in the absence of stimulation (transudate) and after stimulation of chamber tissue with the mild irritant carrageenan (exudate). PBZ pharmacokinetics after i.v. dosage was characterized by slow clearance (1.29 mL/kg/h), long-terminal half-life (53.4 h), low distribution volume (0.09 L/kg) and low concentrations in plasma of the metabolite oxyphenbutazone (OPBZ), confirming previously published data for adult cattle. After oral dosage bioavailability (F) was 66%. Passage into exudate was slow and limited, and penetration into transudate was even slower and more limited; area under curve values for plasma, exudate and transudate after i.v. dosage were 3604, 1117 and 766 microg h/mL and corresponding values after oral dosage were 2435, 647 and 486 microg h/mL. These concentrations were approximately 15-20 (plasma) and nine (exudate) times greater than those previously reported in horses (receiving the same dose rate of PBZ). In the horse, the lower concentrations had produced marked inhibition of eicosanoid synthesis and suppressed the inflammatory response. The higher concentrations in calves were insufficient to inhibit significantly exudate prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and beta-glucuronidase concentrations and exudate leucocyte numbers, serum thromboxane B2 (TxB2), and bradykinin-induced skin swelling. These differences from the horse might be the result of: (a) the presence in equine biological fluids of higher concentrations than in calves of the active PBZ metabolite, OPBZ; (b) a greater degree of binding of PBZ to plasma protein in calves; (c) species differences in the sensitivity to PBZ of the cyclo-oxygenase (COX) isoenzymes, COX-1 and COX-2 or; (d) a combination of these factors. To achieve clinical efficacy with single doses of PBZ in calves, higher dosages than 4.4 mg/kg will be probably required.     

Influence of oxytetracycline on carprofen pharmacodynamics and pharmacokinetics in calves

A tissue cage model of inflammation in calves was used to determine the pharmacokinetic and pharmacodynamic properties of individual carprofen enantiomers, following the administration of the racemate. RS(±) carprofen was administered subcutaneously both alone and in combination with intramuscularly administered oxytetracycline in a four‐period crossover study. Oxytetracycline did not influence the pharmacokinetics of R(?) and S(+) carprofen enantiomers, except for a lower maximum concentration (C_max) of S(+) carprofen in serum after co‐administration with oxytetracycline. S(+) enantiomer means for area under the serum concentration–time curve (AUC_0–96h were 136.9 and 128.3 μg·h/mL and means for the terminal half‐life (T_½k₁₀) were = 12.9 and 17.3 h for carprofen alone and in combination with oxytetracycline, respectively. S(+) carprofen AUC_0–96h in both carprofen treatments and T_½k₁₀ for carprofen alone were lower (P < 0.05) than R(?) carprofen values, indicating a small degree of enantioselectivity in the disposition of the enantiomers. Carprofen inhibition of serum thromboxane B₂ ex vivo was small and significant only at a few sampling times, whereas in vivo exudate prostaglandin (PG)E₂ synthesis inhibition was greater and achieved overall significance between 36 and 72 h (P < 0.05). Inhibition of PGE₂ correlated with mean time to achieve maximum concentrations in exudate of 54 and 42 h for both carprofen treatments for R(?) and S(+) enantiomers, respectively. Carprofen reduction of zymosan‐induced intradermal swelling was not statistically significant. These data provide a basis for the rational use of carprofen with oxytetracycline in calves and indicate that no alteration to carprofen dosage is required when the drugs are co‐administered.     

Effect of age on the pharmacokinetics of antipyrine in calves

Single doses of 15 mg kg⁻¹ antipyrine were given intravenously to 10 female calves of the black and white breed at one, two, four, six, eight and 12 weeks of age, and the concentrations of antipyrine, 4-hydroxyantipyrine (4-oha), 3-hydroxymethylantipyrine (hma) and norantipyrine (nora) were measured in plasma and urine by high performance liquid chromatography. The first three months of life were characterised by a steady decrease in the apparent volume of distribution (aV_d) and half-life (t_0.5) of antipyrine. The systemic clearance (Cl_s) of antipyrine per unit bodyweight increased significantly between one and 12 weeks of age. Age did not influence the excretion of hma and nora in urine, but the excretion of 4-oha by 12-week-old calves was significantly greater than by one-week-old calves. There was an age-related change in the partial clearances of the antipyrine metabolites when expressed per unit bodyweight.     

Norfloxacin nicotinate pharmacokinetics in unwearied and weaned calves

The pharmacokinetics of norfloxacin nicotinate were investigated in unweaned and weaned calves. Following intravenous administration of 7.5 and 15 mg/kg (calculated as norfloxacin base) the clearance values were 8.5/pm 2.0 or 7.7/pm 1.2mL/min·kg (unweaned calves) and 11.7/pm 3.2 or 16.1/pm 3.3mL/min·kg (weaned calves). Norfloxacin mean residence time and volume of distribution values were 211/pm 33 or 227/pm 41 min (unweaned calves) and 185/pm 79 or 128/pm18 minutes (weaned calves), and 1.8/pm0.3 or 1.7/pm0.1L/kg (unweaned calves) and 2.0/pm0.7 or 2.1/pm0.7L/kg (weaned calves) following administration of the lower and higher dose, respectively. These results indicated that norfloxacin pharmacokinetics were similar at a dose range of 7.5-15 mg/kg. However, a significant difference was observed in clearance, mean residence time and the half-life values between the unweaned and weaned calves. The only major pharmacokinetic parameter which did not show a significant difference between the investigated groups was the volume of distribution. The pharmacokinetic differences between the non-ruminating (unweaned) and ruminating (weaned) animals seemed to result from changes in drug clearance. The absorption rate after intramuscular administration appeared to change as a result of dose increase. Norfloxacin bioavailability following intramuscular administration ranged from 73 to 106%. The results suggested that larger injection volumes may reduce the extent of absorption.     

Clinical pharmacokinetics of five oral cephalosporins in calves

The minimal inhibitory concentrations (MIC) of cephalexin, cephradine, cefaclor, cefatrizine and cefadroxil for Salmonella species, Escherichia coli and Pasteurella multocida isolated previously from young calves were determined. The MIC90 values for cephalexin, cephradine and cefadroxil ranged between 3.12 micrograms ml-1 and 12.5 micrograms ml-1, whereas those of cefatrizine and cefaclor were 3.12 micrograms ml-1 and 0.78 microgram ml-1, respectively. Each drug was administered intravenously and orally to groups of pre-ruminating calves and orally to early ruminating calves. Although the pharmacokinetic characteristics of the drugs after intravenous injection were similar to other beta-lactam antibiotics, significant differences between the cephalosporins examined were found in respect of certain kinetic parameters. The drugs showed rapid absorption into the systemic circulation after oral administration to pre-ruminating calves but the elimination half-life values (t1/2 beta) varied between three hours (cefaclor and cefadroxil) and nine hours (cefatrizine). The bioavailability of the drugs was about 35 per cent of the administered dose. Co-administration of probenecid with each antibiotic caused a twofold or greater increase in peak serum drug concentrations (Cmax) but the effect on t1/2 beta was variable. Cephalexin, cephradine and cefaclor given to the ruminating calves resulted in very low serum or plasma concentrations and their use should be restricted to younger calves. Cefadroxil was found to give the highest serum concentrations in this age group but had significantly lower bioavailability when compared with the unweaned calves. Provisional oral dosage regimens were computed for each cephalosporin on the basis of the MIC data and the kinetic parameters derived from intravenous and oral drug administration.     

Probenecid: its chromatographic determination, plasma protein binding, and in vivo pharmacokinetics in dogs

Pharmacokinetics (PK) of probenecid including plasma probenecid concentrations, in vitro plasma protein binding properties, and in vivo PK parameters were determined in dogs. Probenecid concentrations were best determined by HPLC, which showed good linearity and good recovery with simple plasma preparation. The quantification limit of probenecid was approximately 50 ng/ml at S/N ratio = 3, by simple procedure with HCl and methanol treatment. Probenecid showed two types of binding characteristics, i.e., high-affinity with low-capacity and low-affinity with high-capacity binding. This result indicated 80-88% of probenecid was bound to plasma protein(s) at observed concentrations (< 80 microg/ml) in vivo at an intravenous dose of 20 mg/kg. Plasma probenecid concentration-time profile following i.v. administration in dogs showed biphasic decline and well fitted a two-compartment open model. The total body clearance was 0.34 +/- 0.04 ml/min/kg, volume of distribution at steady-state was 0.46 +/- 0.07 l/kg, elimination half-life was 18 +/- 6 hr, and mean residence time (MRT) was 23 +/- 6 hr. Since probenecid has been known as a potent inhibitor of renal tubular excretion of acidic drugs and highly binds to plasma proteins, our observation in relation to plasma protein binding and PK parameters will serve as the basic information concerning drug-drug interactions in dogs and in other mammalian species.     

Comparative pharmacokinetics of ampicillin-sulbactam combination in calves and sheep

The pharmacokinetics of ampicillin and sulbactam administered in combination were studied in calves and sheep. The animals were administered an aqueous solution of ampicillin/sulbactam (2: 1, w/w) intravenously and intramuscularly at doses of 13.2 and 6.6 mg.kg^-1, respectively. A microbiological method was used to detect ampicillin, and HPLC was used to detect sulbactam in serum. Following intravenous (i, v.) administration, the distribution phases were rapid and similar (about 15 min) for both drugs in both species, whereas sulbactam in calves and ampicillin in sheep showed a faster elimination rate. After intramuscular (i.m.) administration both drugs showed peak concentrations higher in calves than in sheep: the peak time of sulbactam was shorter in calves than in sheep. No other significant differences in the pharmacokinetics of the combination were observed between the species after i.m. injection. The mean residence and absorption times, calculated by non-compartmental analysis, for both calves and sheep suggested that the differences in ampicillin and sulbactam phgrmacokinetics could be attributable to the different molecular structures.     

Comparative pharmacokinetics of amikacin sulphate in calves and sheep

The pharmacokinetics of amikacin sulphate were investigated in calves and sheep. Five animals of each species were given 7.5 mg kg-1 intravenously and intramuscularly. After intravenous administration the pharmacokinetic parameters significantly different (P less than 0.01) between calves (first value) and sheep (second value), were: the initial concentration (87.05, 146.6 micrograms ml-1), the apparent distribution volume (350, 200 ml kg-1), the area under curve (5512, 11,018 min micrograms ml-1) and the clearance (1.5, 0.7 ml min-1 kg-1). After dosing intramuscularly the peak concentration (23.5, 34.36 micrograms ml-1), the peak time (45, 75 min) and the area under curve (5458, 9191 min micrograms ml-1) were significantly different (P less than 0.01). No significant differences were observed in the terminal halflife values, suggesting that elimination rate was independent of both route of administration and animal species. The drug in aqueous solution showed a good bioavailability in both animal species (about 0.87 in sheep and greater than 0.99 in calves) despite the greater serum concentrations always attained in sheep.     

The pharmacokinetics of transdermal flunixin meglumine in Holstein calves

This study describes the pharmacokinetics of topical and intravenous (IV) flunixin meglumine in Holstein calves. Eight male Holsteins calves, aged 6 to 8 weeks, were administered flunixin at a dose of 2.2 mg/kg intravenously. Following a 10‐day washout period, calves were dosed with flunixin at 3.33 mg/kg topically (transdermal). Blood samples were collected at predetermined times from 0 to 48 h for the intravenous portions and 0 to 72 h following topical dosing. Plasma drug concentrations were determined using liquid chromatography with mass spectroscopy. Pharmacokinetic analysis was completed using noncompartmental methods. The mean bioavailability of topical flunixin was calculated to be 48%. The mean AUC for flunixin was determined to be 13.9 h × ug/mL for IV administration and 10.1 h × ug/mL for topical administration. The mean half‐life for topical flunixin was 6.42 h and 4.99 h for the intravenous route. The C_max following topical application of flunixin was 1.17 μg/mL. The time to maximum concentration was 2.14 h. Mean residence time (MRT) following IV injection was 4.38 h and 8.36 h after topical administration. In conclusion, flunixin when administered as a topical preparation is rapidly absorbed and has longer half‐life compared to IV administration.     

The pharmacokinetics and residues of clenbuterol in veal calves.

Seven female Brown Swiss calves were used to study the pharmacokinetics of clenbuterol after an effective anabolic dosage of 5 micrograms/kg of BW was given twice daily for 3 wk. Analyses of clenbuterol concentrations in different tissues was done by enzyme immunoassay (EIA). Tissue samples were taken from three calves on the last day of administration and from two more after 3.5 or 14 d of clenbuterol withdrawal. The rate of clenbuterol elimination was dependent on time and tissue. Clenbuterol concentrations in the lung dropped from a mean of 76 ng/g to a level of less than .08 ng/g after 14 d, whereas in the liver the clenbuterol concentrations decreased from 46 ng/g to .6 ng/g within 14 d of withdrawal. Highest levels were always found in the eye: 118 ng/g, 57.5 ng/g, and 15.1 ng/g after 0, 3.5, and 14 d of withdrawal, respectively. These data reveal that different compartments contribute to the elimination of clenbuterol; therefore, concentrations in urine do not follow first order kinetics. An initial rapid decline in the concentration of clenbuterol in urine with a half-life of 10 h is followed by a slower elimination with a half-life of about 2.5 d. Treatments using the anabolic dose of 5 micrograms/kg of BW require longer withdrawal times than the therapeutic dose (.8 micrograms/kg BW).     

Comparison of pharmacokinetics of sodium and lysine cephalexin in calves

The pharmacokinetics of sodium and lysine cephalexins were investigated after intravenous and intramuscular administration of a single dose rate of 30 mg.kg-1 body weight in calves. The data for the two salts administered intravenously were pooled, the resulting pharmacokinetic disposition of cephalexin indicating a distribution half-time (t1/2 alpha) and an elimination half-time (t1/2 beta) of 9.78 and 62.0 min, respectively. Following intramuscular administration some pharmacokinetic differences were recorded between the cephalexin preparations: lysine cephalexin was more rapidly eliminated (t1/2kel = 55.2 min) than sodium cephalexin (t1/2kel = 89.8 min), although the peak blood level was higher and attained after a longer time with lysine cephalexin.     

The pharmacokinetics of ketamine administered intravenously in calves and the modifying effect of premedication with xylazine hydrochloride

Ketamine hydrochloride was administered intravenously to unpremedicated and xylazine-treated calves. The plasma concentrations of ketamine and norketamine were measured at several time intervals after drug administration and the data were fitted to a two-compartment open model. In unpremedicated female calves the distribution and elimination half-lives averaged 6.9 and 60.5 min, respectively. The volume of the central compartment was 1.21 1/kg and the peripheral compartment was 4.04 1/kg. Total body clearance of ketamine averaged 40.4 ml/ min/kg. Premedication with xylazine, whilst not affecting the half-lives signifi-candy, reduced volumes of distribution and the clearance rate of the drug by approximately 50%. The results for the male calves which were premedicated were intermediate between the two groups of female calves.     

Comparative pharmacokinetics of chlortetracycline in milk-fed versus conventionally fed calves

Plasma and tissue concentration and pharmacokinetics of chlortetracycline (CTC) was determined in milk-fed and conventionally fed Holstein calves. A two-compartment open model was used after a single intravenous dose (11 mgn CTC/kg body weight). There were no significant differences between dietary treatments. The drug was rapidly distributed from plasma into the peripheral compartment but was slowly eliminated, with detectable concentration of CTC continuing for 72 h after dosing. A single-compartment model was used after a single oral dose (22 mg CTC/kg body weight). All but four of the kinetic parameters were significantly different for the two dietary treatments. Milk-fed calves had a larger area under the plasma level curve, a larger fraction of the dose absorbed, a smaller volume of distribution and a smaller overall body clearance rate. Estimated recovery of CTC in the urine of the milk-fed calves was greater, regardless of route of administration. The concentration of CTC in tissues following an oral dose was greatest in kidney, followed by liver, heart, skeletal muscle, spleen and brain. Tissue depletion of CTC closely paralleled the decline in plasma concentration.     

Influence of marbofloxacin on the pharmacokinetics and pharmacodynamics of tolfenamic acid in calves

Pharmacokinetic and pharmacodynamic properties of tolfenamic acid (TA) in calves were determined in serum and fluids of inflamed (carrageenan administered) and non-inflamed subcutaneously implanted tissue cages after intramuscular administration both alone and in combination with marbofloxacin (MB). MB significantly altered the pharmacokinetics of TA: mean values were Cmax = 2.14 and 1.64 microg/mL, AUC = 27.38 and 16.80 microg.h/mL, Vd(area)/F = 0.87 and 1.17 L/kg, and ClB/F = 0.074 and 0.128 L/kg/h, respectively, after administration of TA alone and TA + MB. T(1/2)K10 and MRT were not significantly different for the two treatments. The pharmacodynamic properties of TA were not influenced by MB co-administration, in spite of the alterations in some TA pharmacokinetic parameters. TA inhibited prostaglandin E2 (PGE2) synthesis in vivo in inflammatory exudate by 50-88% for up to 48 h after both TA treatments. Inhibition of synthesis of serum thromboxane B2 (TxB2) ex vivo ranged from 40 to 85% up to 24 h after both TA and TA + MB. From the derived pharmacokinetic and eicosanoid inhibition data for TA, pharmacodynamic parameters for serum TxB2 and exudate PGE2 inhibition expressing efficacy (Emax = 78.1 and 97.5%), potency (IC50 = 0.256 and 0.265 microg/mL), sensitivity (N = 1.96 and 2.29) and the pharmacokinetic parameter equilibration time (t(1/2)K(e0) = 0.695 and 24.0 h), respectively, were determined. In this model TA was a nonselective inhibitor of cyclo-oxygenase (COX) (COX-1:COX-2 IC50 ratio = 1.37). TA, both alone and co-administered with MB, did not affect leucocyte numbers in exudate, transudate or blood. Partial attenuation of skin temperature rise over inflamed tissue cages and reduction of zymosan-induced skin swelling were recorded after administration of TA and TA + MB with no significant differences between the two treatments. These data provide a basis for the rational use of TA in combination with MB in calf medicine.