Polysaccharide peptides from COV-1 strain of Coriolus versicolor inhibit tolbutamide 4-hydroxylation in the rat in vitro and in vivo.
Polysaccharide peptide (PSP), isolated from COV-1 strain of Coriolus versicolor, is commonly used as an adjunct in cancer chemotherapy in China. In this study, the effects of whole PSP extract and water extract of PSP on 4-hydroxylation of tolbutamide were investigated in rat liver microsomes in vitro and in vivo in the rat. Both the whole PSP extract and the water soluble fraction (0.5-20 microM) decreased the metabolism of tolbutamide to 4-hydroxytolbutamide in vitro. Enzyme kinetics studies showed that PSP inhibited tolbutamide 4-hydroxylase activity in a competitive, concentration-dependent manner. The whole PSP extract had a Ki value of 12.6 microM and IC50 at 18.4 microM, while the water extract had a Ki value of 6.9 microM and IC50 at 9.8 microM. Sulphaphenazole, a specific human CYP2C9 inhibitor, showed a Ki value of 30.8 microM and IC50 at 44.0 microM in the test system. In the pharmacokinetic studies in vivo, acute PSP (4 micromol/kg, i.p.) treatment did not produce significant changes in tolbutamide clearance, but produced a decrease in the Cinitial (7.4%) and an increase in the Vd (7.4%). Sub-chronic pre-treatment of PSP (1-2 micromol/kg/day, i.p.) for three days did not affect the clearance and AUC of tolbutamide, but the Cinitial was decreased, together with increases in the T1/2, and Vd. The formation of 4-hydroxytolbutamide in vivo was decreased in both acute and sub-chronic studies. Taken together, this study demonstrated the PSP can inhibit tolbutamide 4-hydroxylation both in vitro and in vivo. Despite the fact that CYP isoforms that metabolise tolbutamide are different between rat and human liver due to different catalytic characteristics, and rat studies may not be directly extrapolatable to man, the concomitant use of PSP with other CYP2C substrates should be carefully monitored.
Yeung
John H K
JH
Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China. johnyeung@cuhk.edu.hk
Chan
Siu-Lung
SL
Or
Penelope M Y
PM
D000818:Animals; D001487:Basidiomycota / Q000737:chemistry*; D002240:Carbohydrate Sequence; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006900:Hydroxylation / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D007527:Isoenzymes; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D011509:Proteoglycans / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013426:Sulfaphenazole / Q000494:pharmacology; D014044:Tolbutamide / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007527:Isoenzymes; D011509:Proteoglycans; C093216:polysaccharide peptide; D013426:Sulfaphenazole; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide