Evaluation of selective competitive binding of basic drugs to alpha1-acid glycoprotein variants.

We examined the binding of various basic drugs to the F(1)S and A genetic variants of alpha(1)-acid glycoprotein (AGP), which were isolated from native human commercial AGP (total AGP) by chromatography on an immobilized copper(II) affinity adsorbent. The values of the dissociation constant (K(d)) of some basic drugs with the F(1)S variant in equilibrium dialysis differed characteristically from those with the A variant. The selective binding to these variants was evaluated by measuring the displacement ratio of dicumarol bound to the F(1)S variant or that of acridine orange bound to the A variant, using circular dichroism spectroscopy. There was reasonably good agreement between the K(d) values and displacement ratios. There was a characteristic difference between the values of inhibition constant (K(i)) of basic drugs towards dipyridamole binding to F(1)S and towards disopyramide binding to A in total AGP. We found that the K(i) values for dipyridamole binding were well correlated with the K(d) values for the F(1)S variant, whereas those for disopyramide binding were well correlated with the K(d) values for the A variant. In conclusion, the higher the affinity of basic drugs for AGP, the more they inhibit the binding of other basic drugs, and further, the inhibitory potency depends on the selectivity of binding to the AGP variants.

Soybean fat supplementation controls insulin resistance caused by fat-free total parenteral nutrition.

Conscious young adult male rats were given total parenteral nutrition (TPN) with or without soybean fat for 4 days. Those given fat-free TPN developed severe fatty liver, with hyperglycaemia, hyperinsulinaemia, and hypotriglyceridaemia. These disorders were clearly improved by supplementing TPN with soybean fat, in an amount equivalent to 20% of total calories, and correspondingly reducing glucose. Insulin resistance also developed over a 4-day infusion of fat-free TPN in mature rats. Even after over-night fasting after stopping the TPN infusion, the levels of serum glucose and insulin were higher in the fat-free TPN group than in the control group, and intravenous glucose tolerance test results indicated insulin resistance in the fat-free TPN group. The HOMA-IR index of insulin resistance was significantly improved by supplementation with soybean fat. In conclusion, fat-free TPN infusion induced hyperglycaemia and hyperinsulinaemia, leading to fatty liver and insulin resistance. TPN with glucose should be supplemented with soybean fat emulsion as replacement for part of the glucose calories.

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.