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Contribution of æ 1 ‐acid glycoprotein to plasma protein binding of some basic antimicrobials in pigs
Author(s) -
SON DS.,
HARIYA S.,
SHIMODA M.,
KOKUE E.
Publication year - 1996
Publication title -
journal of veterinary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.527
H-Index - 60
eISSN - 1365-2885
pISSN - 0140-7783
DOI - 10.1111/j.1365-2885.1996.tb00036.x
Subject(s) - chemistry , dissociation constant , albumin , binding constant , mole , nuclear chemistry , stereochemistry , chromatography , binding site , analytical chemistry (journal) , biochemistry , receptor
Protein binding kinetics of basic antimicrobials including trimethoprim (TMP), erythromycin (EM), lincomycin (LM) and clindamycin (CM) were studied using porcine plasma, albumin and æ‐acid glycoprotein (AGP). Rosenthal plots of these basic drugs in porcine plasma suggest saturable and non‐saturable binding. Dissociation constants ( K d ) and binding capacity (B max ) for saturable binding were as follows: TMP, K d = 8.58 μmol/L, B max = 5.26 μmol/L; EM, k d = 2.72 μmol/L, B max = 3.06 μmol/L; LM, k d = 3.96 μmol/L, B max = 6.58 μmol/L and CM, k d = 4.43 μmol/L, B max = 21.7 μmol/L. The proportionality constants (B max 2/ k d 2) for non‐saturable binding were 0.29 in TMP, 0.52 in EM, 0.17 in LM and 3.2 in CM. The k d s of the drugs in porcine AGP solution were determined by a fluorescence quenching method, using 1‐anilino‐8‐naphthalene sulphonate (ANS) as a fluorescent probe: 9.51 μmol/L in TMP, 1.89 μmol/ L in EM, 4.48 μmol/L in LM and 9.69 μmol/L, in CM. Comparable kd values between porcine plasma and AGP solution indicated that AGP is a major saturable binder in porcine plasma. Binding property to porcine albumin presented linearity, showing the following proportionality constants: 0.23 in TMP, 0.38 in EM, 0.01 in LM and 0.76 in CM. The comparable proportionality constants of TMP and EM between porcine plasma and albumin solution indicate that albumin is a major non‐saturable binder, whereas proportionality constants of LM and CM in albumin solution compared to those in porcine plasma were low, implying another non‐saturable binder, i.e. lipoprotein. Simulation curve of drug‐binding percentage vs. AGP concentrations showed that in pigs under a pathologic state, or during early growth stage with high AGP levels, AGP could be a main contributor to drug‐plasma protein binding for all drugs examined. The increase of AGP from normal to pathological concentrations induced a decrease in the unbound fraction: LM > CM > EM > TMP in order of AGP contribution to drug binding. Therefore, the disposition and efficacy of basic antimicrobials which bind to AGP with high affinity could be markedly influenced by altered AGP levels, implying AGP contribution to pharmacokinetics and pharmacodynamics.