Binding Disposition of Local Anesthetic Ropivacaine to .ALPHA.1 -acid Glycoprotein and Interactions with Co-administered Drugs

We examined the influence of basic drugs and protein variants on the binding disposition of ropivacaine to α1-acid glycoprotein (AGP). On doing this, we found the values of the competitive inhibition constant (Ki) for dipyridamole, verapamil, lidocaine and disopyramide with respect to the binding of ropivacaine to commercial AGP (70 mg/dL) to be 2.1, 5.2, 6.0 and 11.0μM, respectively. Also, there was a strong correlation between the fu value and the AGP concentration when ropivacaine was added to plasma samples from ten healthy volunteers (r=0.861). Among the volunteers, eight showed F1S variants and two showed F1 variants without the S variant of AGP. There was no difference in the fu value of ropivacaine between these two groups. However, when ropivacaine was added together with dipyridamole, the fu values of ropivacaine in plasma from volunteers with ES variants were clearly higher than those from volunteers without the S variant. When ropivacaine was added together with disopyramide or lidocaine, however, there was no difference in fu values between these variants.Our results indicate that variability in the effectiveness and/or adverse effects of ropivacaine are caused by changes in fu as a consequence of changes in AGP concentration. They also suggest that in combination therapy, it is also important to consider the AGP variant-dependence of the inhibitory effect of concomitantly administered drugs.