ALPHA-1-ACID GLYCOPROTEIN-BINDING AS A FACTOR IN AGE-RELATED-CHANGES IN THE PHARMACOKINETICS OF TRIMETHOPRIM IN PIGLETS

This study examined the effects of plasma alpha1-acid glycoprotein (AG P) on the protein binding and pharmacokinetics of trimethoprim (TMP) i n piglets. The piglets were given 5 mg/kg of TMP intravenously at 1, 1 4 and 28 days after birth. The plasma AGP level was highest at day 1. Fourteen days after birth, the level decreased by about 90% of that at day 1. The level at 28 days was almost the same as that at 14 days. P lasma protein bindings of TMP depended on the AGP level but not on the albumin level. The percentage of plasma protein binding decreased fro m 85 to 45%, and the AGP level also decreased from 6,000 to 700 mug/ml . The altered protein binding of TMP affected pharmacokinetic paramete rs such as total body clearance (CL(tot)), distribution volume and the refore the elimination rate constant. These parameters correlated well with the percentage binding to plasma proteins. Maturational developm ent in the capacity to eliminate TMP was also indicated by the increas e in total body clearance of unbound drug (CL(totub)), which directly reflects the elimination capacity of the body. However, its contributi on to the increase in CL(tot) was considered not to be large. CL(totub ) increased twofold 14 days after birth, whereas CL(tot) increased abo ut ninefold. The increase in CL(tot) therefore, may result from both t he maturational development in elimination capacity and the AGP-depend ent decrease in plasma protein binding. It is concluded that the decre ase in plasma AGP level observed in piglets is one of major factors af fecting the pharmacokinetics of TMP.