Animal & Veterinary
COMPARATIVE PHARMACOKINETICS IN DIFFERENT PRODUCTION CLASSES OF CATTLE
by Ian F. De Veau, Ph.D.
FDA Veterinarian Newsletter September/October 1999 Volume XIV, No V
Increasing attention has been directed to the influences of gender and physiological states, such as pregnancy and lactation, on the pharmacokinetics of human drugs. Prior to 1993, FDA guidelines for the clinical evaluation of human drugs recommended that women of childbearing age be excluded from phase 1 and early phase 2 clinical studies until reproductive toxicity studies were conducted and some evidence of effectiveness had become available. Though the guideline did not exclude using women as test subjects in later clinical studies, its effect was to do just that. This policy raised ethical, legal, and scientific questions about its suitability. One of the concerns was that the physiological, metabolic, and hormonal differences between women and men were such that it would be difficult to conclude how well the pharmacokinetic behavior of a drug in women could be predicted by its pharmacokinetic behavior in men. Not knowing about a drug's pharmacokinetic profile in women means not knowing its efficacy, since the effectiveness of most drug treatments is correlated to blood levels. It has been shown that significant differences between women and men in drug elimination are common (Wilson, 1984 and Loebstein et al., 1997). In 1993, FDA reversed its position concerning the use of women in early clinical trials to address potential gender differences in drug elimination. This change is part of an overall trend in FDA policy to broaden the human population base used routinely in clinical trials. FDA's goal is to address the potential impact of gender, age, and ethnic background on the pharmacokinetics and the pharmacodynamics of human drugs.
Gender and physiological state also influence the pharmacokinetic parameters of veterinary drugs. Witkamp et al. (1992) reported that the half-life of sulfamethazine was about 75 percent and 40 percent lower in female goats and cattle, respectively, than in males of the same species. The half-life of thiamphenicol is shorter in 4-6 month old beef and dairy calves compared to mature lactating dairy cows (Abdennebi et al., 1994). Furthermore, Bengtsson et al. (1997) found statistical differences between pregnant and lactating sheep in the clearance, volume of distribution, and elimination half-life of penicillin-G.
This potential influence of gender and physiology on drug elimination could impact the regulation of drug use in cattle. As a hypothetical example, a drug sponsor submits a new parasiticide to CVM for approval. The application states that the drug is intended only for use in beef cattle. The sponsor needs to provide pharmacokinetic data for only beef animals. This would include either steers (castrated males) or non-lactating beef cows. The sponsor need not perform any pharmacokinetic studies on lactating dairy cows. Let's further say that, upon review of the submitted data, CVM determines that the drug is safe and effective for treatment of parasites in beef cattle and does not represent a human food or environmental safety risk. The drug is approved. What if, at a later date, the drug sponsor seeks approval for use of this drug to treat the same condition in lactating dairy cows? Do the pharmacokinetic data obtained from beef cattle adequately predict drug elimination in lactating dairy animals, or should CVM require the drug sponsor to generate additional drug elimination data to demonstrate safety and efficacy for this new production class? CVM's Office of Research is investigating the existence of pharmacokinetic differences between beef and dairy cattle.
Phenylbutazone was the first drug studied by the Office of Research to investigate pharmacokinetic differences between bovine production classes. Phenylbutazone is a non-steroidal anti-inflammatory and anti-pyretic drug approved for use in horses. However, phenylbutazone can have severe side effects in humans, and it is not approved for use in any food-producing animal because of food safety issues. In spite of this, there is evidence of its extra-label use in cattle. Phenylbutazone is used to treat mastitis in lactating dairy cows (Dascanio et al., 1995 and Shpigel et al., 1998); bacterial infections in neonatal calves (Semrad et al., 1993); and musculoskeletal disorders in steers and bulls (Williams et al., 1990). It is a lipophilic drug that is highly plasma protein bound (> 98 percent, Boudinot et al., 1990) and undergoes minimal biotransformation in cattle (Lees et al., 1988). There is evidence that phenylbutazone elimination half-life is different among different age groups of cattle. For example, the elimination half-lives for neonatal calves, dry dairy cows, and mature bulls are 207 (Semrad et al., 1993), 40 (Lee et al., 1988), and 62 hours (Williams et al., 1990), respectively. To the best of our knowledge, no one has compared two different production classes with respect to phenylbutazone pharmacokinetics.
Phenylbutazone was administered to a group of lactating dairy cows at a dosage of 6 mg/kg body weight. Plasma and milk samples were taken periodically and analyzed for phenylbutazone. The clearance, volume of distribution at steady state, and elimination half-life were 3 mL/hr/kg body weight, 147 mL/kg body weight, and 40 ± 6 hr, respectively (De Veau et al., 1998). These values were similar to that determined for dry dairy cows (Lee et al., 1988). Phenylbutazone was excreted into the milk at levels several times greater than could be predicted by simple diffusion. One possible explanation for the higher than predicted levels of phenylbutazone in milk would be significant phenylbutazone binding to milk proteins. Phenylbutazone elimination half-life was determined from milk data and was calculated to be 47 ± 4 hr. Mammary clearance of phenylbutazone was 0.009 mL/hr/kg body weight, or about 0.34 percent of total body clearance.
A pharmacokinetic study on a group of beef steers, using the same dosage of phenylbutazone, was also completed. Plasma samples were taken periodically and analyzed for phenylbutazone. Pharmacokinetic parameters were calculated. The results are being reviewed by Office of Research management and should be available for publication shortly.
Additional pharmacokinetic studies are currently being conducted at Office of Research using several model drugs of differing lipophilicity, plasma protein binding, and mode and degree of biotransformation. This should give CVM a more complete understanding on predicting when a drug is likely to be eliminated differently by the two production classes of cattle.
- Abdennebi, E.H., Sawchuk, R.J., & Stowe, C.M. (1994) Thiamphenicol pharmacokinetics in beef and dairy cattle. Journal of Veterinary Pharmacology and Therapeutics, 17: 365-368.
- Bengtsson, B., Jacobsson, S.-O., Luthman, J. & Franklin, A. (1997) Pharmacokinetics of penicillin-G in ewes and cows in late pregnancy and in early lactation. Journal of Veterinary Pharmacology and Therapeutics, 20: 258-261.
- Boudinot, F.D., Williams, R.J., & Smith, J.A. (1990) Effect of non-linear plasma protein binding on unbound and total plasma phenylbutazone concentrations in cows. Journal of Veterinary Pharmacology and Therapeutics, 13: 132-136
- Dascanio, J.J., Mechor, G.D., Grohn, Y.T., Kenny, D.G., Booker, C.A., Thompson, P., Chiffelle, C.L., Musser, J.M.M. & Warnick, L.D. (1995) Effect of phenylbutazone and flunixin meglumine on acute toxic mastitis in dairy cows. American Journal of Veterinary Research, 56: 1213-1218.
- De Veau, E.J.I., W. Pedersoli, R. Cullison, and J. Baker. 1998. Pharmacokinetics of Phenylbutazone in Plasma and Milk of Lactating Dairy Cows. Journal of Veterinary Pharmacology and Therapeutics 21: 437-443.
- Lees, P., Ayliffe, T. & Maitho, T.E. (1988) Pharmacokinetics, metabolism and excretion of phenylbutazone in cattle following intravenous, intramuscular and oral administration. Research in Veterinary Science, 44: 57-67.
- Loebstein, R., Lalkin, A., & Koren, G. (1997). Pharmacokinetic changes during pregnancy and their clinical relevance. Clinical Pharmacokinetics, 33: 328-343.
- Semrad, S.D., McClure, J.T., Sams, R.A. & Kaminski, L.M. (1993) Pharmacokinetics and effects of repeated administration of phenylbutazone in neonatal calves. American Journal of Veterinary Research, 54: 1906-1911.
- Shpigel, N.Y., Winkler, M., Ziv, G. & Saran, A. (1998) Relationship between in vitro sensitivity of coliform pathogens in the udder and the outcome of treatment for clinical mastitis. Veterinary Record, 142: 135-137.
- Witkamp, R.F., Yun, H.-I., van’t Klooster, G.A.E., van Mosel, J.F., van Mosel, M., Ensink, J.M., Noordhoek, J. & van Miert, A.S.J.P.A.M. (1992) Comparative aspects and sex differentiation of plasma sulfamethazine elimination and metabolite formation in rats, rabbits, dwarf goats, and cattle. American Journal of Veterinary Research, 53: 1830-1835.
- Williams, R.J., Boudinot, F.D., Smith, J.A., & Knight, A.P. (1990) Pharmacokinetics of phenylbutazone given intravenously or orally to mature Holstein bulls. American Journal of Veterinary Research, 51: 367-370.
- Wilson, K. (1984). Sex-related differences in drug disposition in man. Clinical Pharmacokinetics, 9: 189-202.