Study On The Pharmacokinetics Of S-omerprazole Capsules In Healthy Volunteers And Enantioselective HPLC Determination Of Omeprazole And Its Metabolites

Omerprazole , a substituted benzimidazole, is an inhibitor of proton-pump suppressed the secretion of gastric acid by the inhibition of the H⁺-K⁺-ATPase system.Omerprazole is widely used to treat Zollinger-Ellision syndrome and peptic ulcer disease.It has greater antisecretory activity than histamine H2-receptor antagonists. S-omerprazole , one of the optical isomers of omerprazole , has higher mean AUC and longer t_1/2. time than omerprazole in human body.S-omerprazole produces greater activities in treating acid-related diseases. The author has developed a gradient elution HPLC method for determination of S-omerprazole and its metabolites. The phamacokinetics of S-omerprazole capsules in human were studied.A new method of chiral separation of omeprazole and its metabolites was studied.It has not been reported yet in literature.A gradient elution HPLC method is established to measure S-omerprazole and its two metabolites in plasma. M3, an unkown metabolites of S-omeprazole is not yet reported in china,was determinated in my study. S-omerprazole and its metabolites were extracted from plasma samples with phosphate buffer andn-propanol-dichlorometnane(l:19). HPLC separation was achived by gradient elution on an Intersil C₁₈(250× 4.6mm ID, 5 μ m) column with a mobile phase composed of methanol and 0.03 mol/L phosphate buffer(pH 7.3).The flow rate was 1.0ml/min and the UV detector was set at 304 nm.The column temperature was 25 °C. S-omerprazole and its metabolites were well separated under the chromatographic condition. The linear range of S-omerprazole and its metabolites were 0.0078-2 mg/L,0.0039² mg/L and 0.0098-5 mg/L, respectively ( r =0.9999,0.9999,0.9997). The limit of detection were 0.0078,0.0039 and 0.0098 mg/L ? The recovery were 99.6—103.1%,88.7—101.0% and 97.8—106.0%, respectivelycThe pharmacokinetics of S-omeprazole capsules were investigated in 8 healthy human volunteers .The volunteers were divided into 2 groups, in which 2 male and 2 female included. The main pharmacokinetic parameters are following:S-omerprazole: 20mg dose, Tmax was 2.50±0.71h; Cmaxwas 0.93 + 0.31mg/L; ti/2. was 1.47±0.57h; AUC wasl.83 + 0.88 mg/L'h; lag time was 0.69±0.21ho60mg dose, Tmax was 1.81±0.80h; Cmaxwas 1.62±0.76mg/L; t^. was 1.24 + 0.53h; AUC was 3.68±0.98mg/L'h; lag time was 0.41 ±0.28hoomerprazole sulfone: 20mg dose, Tmax was 3.75 ± 1.85h; Cmax was 0.34 ±0.25mg/L; ti/2. was 3.38+ 1.45h; AUC was 2.78±3.75mg/L*h; lag time was 0.93 ±0.23h=60mg dose, Tmax was 2.75 +0.65h; Cmax was 0.74 + 0.52mg/L; t)/2u was 3.87+1.31h; AUC was 6.57±5.84mg/L'h; lag time was 0.70±0.09h=hydroxyomeprazole: 20mg dose, Tmax was 2.13 ±0.75h; Cmax was 0.36 + 0.21mg/L; ti/2. was 2.07+ 1.22h; AUC was 0.76 + 0.23mg/L?h; lag time was 0.67±0.20ho60mg dose, Tmax was 2.25 +0.65h; Cmax was 0.48 + 0.27mg/L; ti/2-was 1.34+0.52h; AUC was 1.15 + 0.41mg/L?h; lag time was 0.60±0.14h.A steroselective HPLC assay was developed to isolate omeprazole enantiomers using ChroTech (100mm X 4mm) AGP chiral column.The mobile phase was methanol-phosphate buffer (12.8:87), containing n-propanol 0.2% and flow rate was 0.9ml/min. The column temperature was 25 °C . A good separation of R-omeprazole, S-omeprazole, IS,R-hydroxyomeprazole , S-hydroxyomeprazole , and omerprazole sulfone can be achived.This method was used to analyze the plasma of volunteers.The results shows that S-omeprazole can not be metabolized to R- hydroxyomeprazole and R-omeprazole can not be found in the plasma of volunteers.This method has not been reported in literature so far.