Effects of age on the pharmacokinetics of single dose ceftiofur sodium administered intramuscularly or intravenously to cattle.
The effects of maturation on the intravenous (IV) and intramuscular (IM) pharmacokinetics of ceftiofur sodium following a dose of 2.2 mg ceftiofur equivalents/kg body weight were evaluated in 16 one-day-old Holstein bull calves (33-53 kg body weight initially; Group 1) and 14 six-month-old Holstein steers (217-276 kg body weight initially; Group 2). Group 1 calves were fed unmedicated milk replacer until 30 days of age and were then converted to the same roughag/concentrate diet as Group 2. Groups 1-IV and 2-IV received ceftiofur sodium IV, and Groups 1-IM and 2-IM received ceftiofur sodium IM. Group 1 calves were dosed at 7 days of age and at 1 and 3 months of age; group 2 calves were dosed at 6 and 9 months of age. Blood samples were obtained serially from each calf, and plasma samples were analysed using an HPLC assay that converts ceftiofur and all desfuroylceftiofur metabolites to desfuroylceftiofur acetamide. Cmax values were similar in all calves, and were no higher in younger calves than in older calves. Plasma concentrations remained above 0.150 microgram ceftiofur free acid equivalents/mliter for 72 h in 7-day-old calves, but were less than 0.150 microgram/mliter within 48 h following IV or IM injection for 6- and 9-month-old calves. Intramuscular bioavailability, assessed by comparing the model-derived area under the curve (AUCmod) from IM and IV injection at each age, appeared to be complete. After IV administration, the AUCmod in 7-day-old and 1-month-old calves (126.92 +/- 21.1 micrograms.h/mliter and 135.0 +/- 21.6 micrograms.h/mliter, respectively) was significantly larger than in 3-, 6- and 9-month-old calves (74.0 +/- 10.7 micrograms.h/mliter, 61.0 +/- 17.7 micrograms.h/mliter and 68.5 +/- 12.8 micrograms.h/mliter, respectively; P < 0.0001). The Vd(ss) decreased linearly within the first 3 months of life in cattle (0.345 +/- 0.0616 L/kg, 0.335 +/- 0.919 L/kg and 0.284 +/- 0.0490 L/kg, respectively; P = 0.031), indicative of the decreasing extracellular fluid volume in maturing cattle. The ClB was significantly smaller in 7-day-old and 1-month-old calves (0.0178 +/- 0.00325 L/h.kg and 0.0167 +/- 0.00310 L/h.kg, respectively) than in 3-, 6- and 9-month-old calves (0.0303 +/- 0.0046 L/h.kg, 0.0398 +/- 0.0149 L/h.kg and 0.0330 +/- 0.00552 L/h.kg, respectively; P < or = 0.001). This observation may be indicative of maturation of the metabolism and/or excretion processes for ceftiofur and desfuroylceftiofur metabolites. The approved dosage regimens for ceftiofur sodium of 1.1-2.2 mg/kg administered once daily for up to 5 consecutive days will provide plasma concentrations above the MIC for bovine respiratory disease pathogens for a longer period of time in neonatal calves than in older calves. Peak plasma concentrations of ceftiofur and desfuroylceftiofur metabolites were no higher in neonatal calves than in more mature cattle, highly suggestive that peak tissue concentrations would be no higher in neonatal calves than in more mature cattle.
Brown
S A
SA
Worldwide Animal Health Product Development, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49001, USA.
Chester
S T
ST
Robb
E J
EJ
D000375:Aging / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D001682:Biological Availability; D002417:Cattle / Q000378:metabolism*; D002511:Cephalosporins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D007273:Injections, Intramuscular / Q000662:veterinary; D007275:Injections, Intravenous / Q000662:veterinary; D007601:Jugular Veins; D008297:Male; D008954:Models, Biological; D011897:Random Allocation; D012015:Reference Standards; D012044:Regression Analysis
D002511:Cephalosporins; C063324:desfuroylceftiofur; C053503:ceftiofur