Involvement of alpha1-acid glycoprotein in inter-individual variation of disposition kinetics of ropivacaine following epidural infusion in off-pump coronary artery bypass grafting.

The influence of drug interaction and protein variants on the binding disposition of ropivacaine to alpha1-acid glycoprotein (AGP) was examined. The subjects were five patients who received epidural infusion of ropivacaine for 24-54 h in off-pump coronary artery bypass grafting followed by drug combination therapy, and 10 healthy volunteers. The post-operation plasma albumin concentration showed little overall change, while the AGP concentration in the five patients decreased for 6 h, then increased gradually to about 3-times the initial value by 54 h. The unbound fraction in plasma (fu) of ropivacaine gradually decreased as the AGP concentration increased, but there was large inter-individual variation among the five patients. In contrast, there was a good correlation between the fu value and AGP concentration when ropivacaine was added to blood samples from the 10 healthy volunteers. Among the volunteers, eight showed F1S variants and two showed F1 variant without S variant of AGP. The fu value of ropivacaine did not differ between these two groups. However, when ropivacaine was added in combination with dipyridamole, the fu values of ropivacaine in blood from volunteers with F1S variants were greater than those in blood from volunteers without S variant. In the case of co-administration of disopyramide or lidocaine, there was no such difference. Among the patients, one showed F1S variants and four showed F1 variant without S variant. The results indicate that variability in the side-effects of therapy with ropivacaine alone is caused by the change of the unbound concentration upon changes in the AGP concentration. However, in combination therapy, it is also important to consider the AGP variant-dependence of the inhibitory effect of concomitantly administered drugs.