Differences in the serum binding determinants of isradipine and darodipine--consequences for serum protein binding in various diseases.
1. Serum protein binding of isradipine and darodipine, and serum concentrations of alpha 1-acid glycoprotein (AAG), albumin (HSA) and non-esterified fatty acids (NEFA) were measured in three groups of patients, I: healthy subjects (n = 20); II: patients with inflammatory disorders (n = 15) and III: patients with hepatic insufficiency (n = 17). 2. AAG was increased significantly in group II patients (P less than 0.001) and decreased in group III patients (P less than 0.001); HSA was decreased significantly in group II and group III patients (P less than 0.001). 3. The free percentage of isradipine was decreased significantly in group II patients (P less than 0.05) and increased in group III patients (P less than 0.05) and multivariate analysis showed that these variations were inversely related to changes in AAG concentration. 4. The free percentage of darodipine was increased significantly in group II and III patients (P less than 0.05) due to a decrease in HSA concentration, as shown by multivariate analysis. 5. The changes in free serum percentages of isradipine and darodipine were inversely related to concomitant changes in the concentration of the serum protein for which they showed the highest affinity, AAG for isradipine and HSA for darodipine, respectively. 6. The unexplained variability in the binding data was greater when AAG was the major determinant of binding (isradipine).
Pinquier
J L
JL
Département de Pharmacologie, Faculté de Médecine de Paris XII, France.
Urien
S
S
Chaumet-Riffaud
P
P
Tillement
J P
JP
D000328:Adult; D001798:Blood Proteins / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007249:Inflammation / Q000378:metabolism; D017275:Isradipine; D008107:Liver Diseases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000097:blood; D009961:Orosomucoid / Q000378:metabolism; D011485:Protein Binding; D011725:Pyridines / Q000097:blood*; D012709:Serum Albumin / Q000378:metabolism
D001798:Blood Proteins; D002121:Calcium Channel Blockers; D005230:Fatty Acids, Nonesterified; D009961:Orosomucoid; D011725:Pyridines; D012709:Serum Albumin; D009543:Nifedipine; C034600:darodipine; D017275:Isradipine