Metabolic Fate of Zolpidem (IV) : Serum and Plasma Protein Binding of zolpidem and Its Transfer into the Blood Cells in Rats, Monkeys and Humans
1993 Volume 8 Issue 4 Pages 445-455
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1993 Volume 8 Issue 4 Pages 445-455
In vitro and in vivo protein binding of zolpidem and its transfer into the blood cells were studied in rats, monkeys and humans. The results are summarized as follows.
1. In a range of 50 to 5000ng/ml, the in vitro percent binding of zolpidem to serum proteins in rats, monkeys and humans was 86.6 ?? 86.9, 92.4 ?? 93.9 and 94.5 ?? 96.0%, respectively.
2. Zolpidem was bound to two classes of sites with different affinities of human serum albumin and α1-acid glycoprotein(AGP). The association constants (Ka, M-1) and binding capacities (NP, M) of zolpidem to these proteins were as follows.
albumin : Ka1=1.8×105, N1P=2.9×10-6, Ka2=4.2×103, N2P=2.1×10-4
α1-AGP : Ka1=6.0×105, N1P=6.3×10-6, Ka2=2.0×104, N2P=2.5×10-5
3. The percent binding of zolpidem in 40mg/ml human albumin solution was 83.4 ?? 85.5% and was almost constant over a range of 50 ?? 5000ng/ml. Zolpidem also was highly bound to human α1-AGP(1mg/ml) but the percent binding of the drug decreased from 83.1% at 50ng/ml to 55.5% at 5000ng/ml. On the other hand, the percent binding of zolpidem in 16mg/ml human globulin solution was 19.5 ?? 21.6%, lower than those in human albumin and α1-AGP solutions. Consequently, albumin and α1-AGP would be responsible for the binding of zolpidem to human serum proteins.
4. The in vivo percent binding of zolpidem was 83.2 ?? 83.8% in rat plasma and 96.0 ?? 96.3% in human plasma. These bound fractions were almost the same as the in vitro bound fractions measured simultaneously, indicating that the in vivo plasma protein binding of zolpidem in rats and humans would not be affected significantly by its metabolites.
5. The transfer rates of zolpidem into the blood cells were 31.6 ?? 36.1% for rats, 30.8 ?? 36.6% for monkeys and 17.5 ?? 18.5% for humans, and no a significant correlation between the free fractions in the plasma and the transfer rates into the blood cells was observed.
