Investigation On The Absorption,Metabolism Mechanism Of Wogonin

Wogonin,5,7-dihydroxy-8-methoxyflavone, is one of the major bioactive flavonoidaglycones isolated from the root of Scutellaria baicalensis Georgi (Fam. Labiatae). In recentyears, wogonin has attracted substantial interest as it possesses antioxidant, antibiosis,anti-inflammatory, anti-hepatitis B virus, cancer-preventive and anticonvulsant effects. Themain objectives of this research were to investigate and clarify the biopharmaceutics andpharmacokinetics characteristics of wogonin, in order to guide design of dosage forms andclinical medication.1. Investigation on the intestinal absorption mechanism of wogoninCaco-2cell and single pass intestine perfusion (SPIP) model were used toinvestigate the intestinal absorption kinetics of wogonin. Wogonin was absorbedthrough the epithelia mostly by paracellular pathway. Temperature, pH and BSAaffected its member transport significantly (P<0.01). Inhibitor of P-gp, pinocytosis, cellmetabolism and multi-drug resistance had not influence on wogonin efflux frombasolateral side to apical side (P>0.05). Wogonin can be absorbed by stomach and different position of rat intestine, and the extent of absorption of upper gastrointestinalis superior to that of below gastrointestinal, which provide a theoretical basis for quickrelease forms or intragastric floating drug delivery system of wogonin.2. Investigation on the bioavailability of wogonin in Beagle dogsWogonin solid dispersions were prepared by the solvent method, and characterizeby methods including dissolution, differential scanning calorimetry and power X-raydiffractometry. The bioavailability assessment in Beagle dogs were assayed byLC-MS/MS. It was indicated that wogonin existed in the solid dispersions at amorphousform and that it possibly interacted with PVP K30via hydrogen bond when the ratio ofdrug to the carrier was1:5. Wogonin plasma concentration versus time curve in Beagledogs showed that the solid dispersion approach was associated with a significantdecrease in tmaxand an evident increase in Cmaxcompared to raw substance wogonin.The absolute bioavailability of wogonin solid dispersion was4%, and comparing to rawsubatance wogonin, the relative bioavalability of wogonin in the solid dispersions was679.9%. The major metabolite wogonin-7β-D-glucuronide (W-7-G) in Beagle dogplasma was confirmed by LC/MSn/DAD technology. Comparing to wogonin soliddispersions, the relative bioavalability of arginine-wogonin solution was81.3%. Theconcentration of W-7-G in dog expressed as wogonin equivalent was twelve times tothat of free wogonin in dog plasma, AUC(0-∞)was amplified to thirty times and MRT(0-t)was extended to2.5times.3. Effects of wogonin administrated by oral on liver microsomal cytochrome P450isoenzyme and mdr1in ratsTo evaluate the induction/inhibition action of wogonin on P450isoenzyme andmdr1in rats, the P450content and mRNA level expression of CYP1A1, CYP2E1,CYP3A1, mdr1a and mdr1b in rat liver after oral administration of wogonin wasanalysed. Male SD rats (n=36) were randomly divided into six groups and givendifferent compounds. P450content in liver microsomes was mearsured by Dual-Beam Spectrophotometric method and mRNA level expression of CYP1A1, CYP2E1,CYP3A1, mdr1a and mdr1b were assayed with RT-PCR. Oral administration ofwogonin at high dose(90mg/kg) can cause significant declined in the content of P450inrat liver, and at low dose(>10mg/kg) can cause decrease significantly in the mRNAlevel expression of CYP1A1.In the present study, the absorption of features in Caco-2cell and SPIP model ofwogonin and the bioavalability of wogonin solid dispersions and arginine-wogonin inBeagle dogs were investigated, which showed that the oral bioavability of wogonin waslow although it had good absorption characters. The reasons were that it suffered poordissolution and strong second-phase metabolism to produce conjugated metabolitewogonin-7-beta-glucuronide under the action of UDP-glucuronytransferase. It deservesto investigate some bioactive on the conjugated substance. Oral administration ofwogonin at high dose can cause significant difference in the content of P450in rat liver,and all given doses can cause decrease significantly in the mRNA level expression ofCYP1A1, which suggested that liver function should be pay attention during long termtreatment with wogonin and avoid combine with the inhibitor of CYP1A1in clinical.