| Objective:To evaluate the bioequivalence and to compare the differences of absorption in vitro and distribution in vivo of Acetaminophen tablets from three different manufacturers, for the possible applications of bioequivalence as quality method of oral preparations; To evaluate the inherent quality of acetaminophen tablets, to provide guideline for its reasonable clinical application and quality evaluation.Methods:Health volunteers were involved in a single dose,3-period cross-over test. 12 healthy male volunteers were divided into 3 groups randomly, and orally given Acetaminophen Tablets A (Anhui Lanyi Pharmaceutical Co., LTD), Tablets B (Shanhai huayuananhuirenji Pharmaceutical Co., LTD), Tablets R (Tianjin Smith Kline) 0.5g, respectively.4ml elbow vein blood were collected before and 0.25,0.5, 0.75,1,1.5,2,2.5,3,4,7,10,15.0h after administration. All blood were heparinized and centrifuged at 4000rpm for 10 minutes, and plasma was separated and stored at-20℃for analysis. Volunteers were taken Tables A, B or R after one or two washing period (7 days or 14 days), in second- or third-period. An HPLC method was used to determine the concentration of acetaminophen in plasma. Diamonsil (diamond) C18 column (5μm,250×4.6mm) with acetonitrile-water (17/83, V/V) as mobile phase at flow rate of 1.0mL·min-1 was used to separate acetaminophen in human plasma. The column temperature was maintained at 25℃, and the detection wavelength was 237nm. Acetaminophen concentration were determined at above chromatography condition and its main pharmacokinetic parameters such as t1/2, AUC0-t, AUC0-∞, were calculated by software of DAS 2.0. Analysis of variance, t-test and (1-2α) confidence interval were used to evaluate the bioequivalence.The dissolution tests of acetaminophen tablets were conducted according to Guidelines affiliated to Chinese Pharmacopoeia and T50 and Td of acetaminophen tablets were calculated for the evaluation of the correlation between dissolution in vitro and absorption in vivo.Results:Acetaminophen was linear in the range of 0.02～25μg-mL-1 (r=0.9966). The Limit of quantification was 0.02μg-mL-1 with the signal to noise ratio≥2 (S/N≥2). The recoveries of acetaminophen at 0.05,1 and 20μg-mL-1 met the requirements. The main acetaminophen pharmacokinetics parameters after oral administration of Acetaminophen Tablet A, B and R were as follows, t1/2 (2.411±0.506) h,(2.849±0.554) h and (2.794±0.543) h, Tmax (1.375±0.598) h,(0.979±1.003) h and (0.979±0.432)h; AUC0～15 (27.243±10.866)μg-mL-1, (27.643±8.008)μg-mL-1·h and (26.755±7.005)μg-mL-1·h; AUC0～∞(27.680±10.944)μg-mL-1·h, (28.363±8.156)μg-mL-1·h and (27.463±7.289)μg-mL-1·h. The dissolution parameters of Acetaminophen Tablet A, B and R were as follows, T5035.221min,3.330min and 2.530min, Td 46.828min,4.590min and 3.620min.Conclusion:1. Multiple factor analysis of variance showed that main pharmacokinetic parameters such as AUC and Cmax, of Acetaminophen Tablets A, B and R had no significant differences between preparations and periods, but there were significant differences between individuals. Further bioequivalence of t-test met the statistical requirements and complied with the bio-equivalent hypothesis, and three acetaminophen A, B, R tablets were bioequivalent.2. The dissolution in vitro of acetaminophen A, B, R tablets and absorption in vivo were well correlated in Cmax, Tmax and T50, Td, which indicated that in a certain extent, dissolution speed in vitro could reflect the absorption rate and degree in vivo.Acetaminophen Tablets B and R were dissoluted to 100% within 15 min, but Tablet A was dissoluted to only 40% in 30 min. here are differences, Tmax of tablet A in vivo was (1.375±0.598) h, tablets B and R were (0.979±1.003) h and (0.979±0.432) h, respectively. |
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