Influence of blood proteins on biomedical analysis. III. Pharmacokinetics and protein binding of gliclazide.

Both pharmacokinetics of total and free gliclazide, a potential hypoglycemic drug, were studied in the healthy (n = 12) and diabetic subjects (n = 11). The blood level of gliclazide was determined by a high-performance liquid chromatography, and the free gliclazide (unbound to proteins) in the serum separated by means of an ultrafiltration. The binding ratio of gliclazide to the blood proteins was about 96% during the periods of 24 hr after administration of the drug. Several pharmacokinetic parameters for the blood gliclazide were derived from the decay curves of the blood drug levels. Each pharmacokinetic parameter was not changed by differences between the healthy and diabetic subjects, the total and free drug levels, and method of administration of the drug; each mean parameter, the elimination rate (ke), the time to peak level (tmax), the elimination half-life (t1/2) and the volume of distribution (Vd beta) was 0.07 hr-1, 2.8 hr, 12.3 hr and 16.4 1 (total level), respectively. The serum from healthy subject receiving orally administered gliclazide was gel-filtered on a Sephadex G-150 column. Each fractionated serum protein of macroglobulin (IgM), gamma-globulin (IgG), albumin (A) and small molecular substances (F), contained gliclazide at average of 3.7, 0.7, 82.3 and 13.2%, respectively, during the periods of 24 hr after administration. In in vitro experiment, it was found that the ratio of gliclazide-albumin binding kept a constant level at 96.5% in the range of normal protein levels (3.3--4.8 g/100 ml). In conclusion, the present result shows that the pharmacokinetics of the total blood level of gliclazide reflect the free gliclazide level, moreover, gliclazide predominantly binds with albumin in the blood and its binding ratio is not constant, but variable according to the dose-relation between the drug and the serum protein.