Excretion of aminopyrine and its metabolites into cows' milk

Abstract

The mechanism by which aminopyrine and its two most common metabolites, 4-aminoantipyrine and N-acetyl-4-aminoantipyrine, pass into cows' milk from the systemic circulation was studied. Healthy lactating dairy cows were infused via the jugular vein with appropriate loading doses followed by a continuous intravenous infusion for a 6-hour period. Blood and milk samples were taken simultaneously at hourly intervals, milk pH values were determined, and drug concentrations were measured. Protein binding was determined in milk and plasma using equilibrium dialysis techniques. Theoretical milk-to-plasma ratios for passive diffusion were calculated on the basis of the pH-pK a partition concept. Experimentally obtained milk-to-plasma ultrafiltrate ratios agreed with theoretical ratios for passive diffusion when aminopyrine and N-acetyl-4-aminoantipyrine were infused. Experimental milk-to-plasma ratios obtained for 4-aminoantipyrine were consistently lower than theoretically calculated ratios. Average experimental ratios of 1.10, 0.50, and 1.00 were obtained for antipyrine, 4-aminoantipyrine, and N-acetyl-4-aminoantipyrine, respectively, with a corresponding average theoretical ratio for passive diffusion of 1.00 in all cases. Changing milk pH did not affect the amount of these compounds that was cleared into the milk. The appearance of aminopyrine and N-acetyl-4-aminoantipyrine in milk can be explained by diffusion concepts. 4-Aminoantipyrine gains access to milk by a process which cannot be explained by simple passive diffusion.