Effect of milking frequency and dosing interval on the pharmacokinetics of cephapirin after intramammary infusion in lactating dairy cows.

The objective was to determine the effect of milking frequency and dosing interval on pharmacokinetics of cephapirin after intramammary infusion. Six healthy Holstein cows were administered cephapirin (200 mg) into 1 rear mammary gland after each of 2 milkings. Cows were milked twice daily (2x) and dosed at a 12-h interval or 3 times daily (3x) and dosed at an 8- or 16-h interval. A duplicated Latin square design allowed each cow to receive all 3 frequency-dose treatments, with intervening washout periods. Concentrations of cephapirin (CEPH) and desacetylcephapirin (DAC) in milk from the treated glands were determined at each milking after infusion using liquid chromatography-mass spectrometry. Data were fitted using 1- and 2-compartment pharmacokinetic models, as well as a noncompartmental model. Cephapirin was rapidly metabolized to DAC in the mammary gland, with DAC being the predominant agent in milk until 48 h after infusion. Pharmacokinetics of CEPH and DAC were similar for all treatment groups, with a 1-compartment model providing a better fit than a 2-compartment model in most instances. Milking frequency did not affect the length of time that milk CEPH concentration exceeded MIC(50) or MIC(90) values (the minimum inhibitory antimicrobial concentration needed to inhibit 50 or 90% of microbial activity, respectively) for common mastitis pathogens, except that cows milked 3x and dosed at a 16-h interval maintained inhibitory concentrations approximately 8 h longer than those dosed at an 8-h interval. Time for milk CEPH concentration to reach the FDA tolerance did not differ among treatment groups [mean +/- SD; 68 +/- 20, 66 +/- 22, and 57 +/- 18 h after last treatment for cows treated at 12, 16, and 8 h, respectively]. Mean residence time for CEPH in the mammary gland was linearly and negatively associated with the volume of milk produced. Calculated CEPH concentration in composite milk from all 4 mammary glands was below the FDA tolerance in all cows by 96 h after the last infusion, which is the labeled withholding time for the preparation used. Our findings suggest that this CEPH preparation, which is labeled for 2 doses 12 h apart, could be administered at a 16-h interval in herds milking 3x, with no significant effect on inhibitory concentrations in milk or withdrawal time; extended withdrawal times would be prudent for cows with very low milk production. Further investigation is needed to determine if milking frequency affects CEPH pharmacokinetics in cows with clinical mastitis.