Pharmacokinetics of phenylbutazone in plasma and milk of lactating dairy cows

Abstract

Phenylbutazone was administered intravenously (i.v.) to a group of four lactating cows at a dosage of 6 mg/kg body weight. Whole plasma, protein-free plasma and milk were analysed for phenylbutazone residues. Pharmacokinetic parameters of total and free phenylbutazone in plasma were calculated using a non compartmental method. In regards to whole plasma data, the mean volume of distribution at steady state (Vss), was 147 mL/kg body weight, with a mean (+/-SEM) terminal elimination half-life (t1/2) of 40+/-6 h. The mean clearance (Cl) was 3 mL/h/kg body weight. The Vss as determined from the protein-free plasma fraction was 50021 mL/kg body weight. This larger Vss of free phenylbutazone compared to total plasma phenylbutazone was attributed to a high degree of plasma protein binding, as well as the greater penetration of free phenylbutazone into tissues. The mean t1/2 of free phenylbutazone was 39+/-5 h. This similarity to the t1/2 estimated from total plasma phenylbutazone data is attributed to an equilibrium between free and plasma phenylbutazone during the terminal elimination phase. Mean t1/2 as determined from milk, applying a urinary excretion rate model, was 47+/-4 h. Milk clearance of phenylbutazone was 0.009 mL/h/kg body weight, or about 0.34% of total body clearance. Furthermore, evidence suggests that phenylbutazone either binds to milk proteins, or is actively transported into milk, as its concentration in milk was greater than that predicted due to a simple partitioning from plasma into milk.

Pharmacokinetics of phenylbutazone in beef steers

“…Furthermore, the drug is highly protein bound in the plasma of cattle (95–99.8%). Slightly different phenylbutazone plasma protein binding is reported among cows, neonatal calves and bulls, but these differences are small and may be attributed to the different means by which the amount of free drug has been determined (Martin et al ., 1984; Lee et al ., 1988; Williams et al ., 1990; Semrad et al ., 1993; De Veau et al ., 1998).…”

“…Phenylbutazone undergoes only limited metabolism in cattle regardless of sex, age and presence or absence of lactation (Martin et al ., 1984; Lee et al ., 1988; Williams et al ., 1990; Semrad et al ., 1993; De Veau et al ., 1998). Furthermore, the drug is highly protein bound in the plasma of cattle (95–99.8%).…”

“…The phenylbutazone pharmacokinetic parameters of steers listed in Tables 1 and 2 for total drug in plasma, t 1/2 , volume of distribution at steady state ( V ss ), volume of distribution during the elimination phase ( V z ), total body clearance (Cl) and AUC are statistically similar to those previously reported for lactating dairy cows (Martin et al ., 1984; De Veau et al ., 1998) as well as nonlactating cows (Eberhardson et al ., 1979; Lee et al ., 1988). The relatively low mean V ss and V z (140 and 144 mL/kg, respectively) to total body water of cattle (570 mL/kg, Ruckenbusch et al ., 1991) reflects the high degree of drug plasma protein binding of phenylbutazone (Fig.…”

“…Recoveries of free phenylbutazone in this range was about 93%. It was previously determined that freezing of plasma samples had no effect on the free plasma phenylbutazone/total plasma phenylbutazone ratio (De Veau, 1998; De Veau et al ., 1998).…”

“…There is considerable evidence that phenylbutazone is used in an extra‐label manner in cattle for the treatment of certain types of mastitis in lactating cows (Dascanio et al ., 1995; Shpigel et al ., 1998), as an anti‐inflammatory and antipyretic in the treatment of bacterial infections in neonatal calves (Semrad et al ., 1993), and to treat various musculoskeletal disorders, including arthritis, in bulls (Williams et al ., 1990). The mean half‐life of phenylbutazone in dairy cows is about 40 h (Eberhardson et al ., 1979; Martin et al ., 1984; Lee et al ., 1988; De Veau et al ., 1998). Neonatal calves have a mean phenylbutazone half‐life of about 207 h (Semrad et al ., 1993), while mature bulls have a mean phenylbutazone half‐life of 62 h (Williams et al ., 1990).…”