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摘要
Objective Based on the physiological engine PBPK model, the prediction accuracy was evaluated with metoprolol sustained-release tablets, aminophylline sustained-release tablets, indapamide sustained-release tablets and omeprazole enteric-coated tablets as tool drugs. Methods The related parameters of aminophylline sustained-release tablets, metoprolol tartrate sustained-release tablets, omeprazole enteric coated tablets and indapamide sustained-release tablets were brought into the physiological driving v1.0 platform to predict the blood concentration and calculate the pharmacokinetic parameters. One tablet (indapamide 1.5 mg, omeprazole 60 mg, metoprolol tartrate 50 mg, aminophylline 100 mg) was given to male beagle dogs. Venous blood collected from dog forelimb before administration and 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 7.0, 9.0, 12.0, 16.0, 24.0, 36.0, 48.0 h after administration. A method of ultra-high performance liquid chromatography triple quadrupole tandem mass spectrometry (UPLC-MS/MS) was established for the determination of beagle dogs' blood drug concentration, and the pharmacokinetic parameters were calculated. The correlation between the predicted results and the measured results was analyzed, and the error of pharmacokinetic parameters was analyzed. Results Successfully established a human-driven human body and beagle dog extrapolation PBPK model, The predicted results of the aminophylline sustained-release tablets, omeprazole enteric-coated tablets, metoprolol sustained-release tablets and indapamide sustained-release tablets in the Beagle dog extrapolation model compared with Beagle's in vivo data, The correlation is 0.9331, 0.9743, 0.9188, 0.9658, The Cmax error of the pharmacokinetic parameter error analysis were 22%, 27%, 10%, 32%, AUC errors were -13%, -9%, -14%, -6%, The error of Tmax were -40%, -15%, 25%, -110%, The error of T1/2 were -17%, -11%, -46%, 52%. The difference between Tmax and t1/2 were large, and the prediction error of omeprazole enteric coated tablets was less than 25%. The Cmax and t1/2 prediction errors of indapamide sustained-release tablets are large, which may be caused by the fact that the total amount of digestive fluid in the digestive tract of dogs is less than that of people, making the dissolution of indapamide more difficult. Conclusion The PBPK model based on physiological engine could accurate predict pharmacokinetic characteristics.of the absorption with metoprolol sustained-release tablets, aminophylline sustained-release tablets (BCSI), class indapamide sustained-release tablets and omeprazole enteric-coated tablets(BCSII).
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