Objective: To analyze biopharmaceutics classification system (BCS) by the parallel artificial membrane permeation assay (PAMPA) and Caco-2 monolayer cell model which was used to study the permeability of lappaconitine hydrobromide(LH)in combination with the determination of solubility, to provide reference for the optimization of related preparations and evaluation of in vitro-in vivo correlation. Methods: The effective permeability (Pe) of LH and metoprolol tartrate in fed state simulated intestinal fluid (FeSSIF, pH 5.0), fasted state simulated intestinal fluid (FaSSIF, pH 6.5) and phosphate buffer solution (pH 7.4) were determined by μFluxTM permeability test system. Meanwhile, the apparent permeation coefficient (Papp) of three model drugs metoprolol tartrate (high permeability), nadolol (low permeability), and digoxin (efflux substrate) were measured using the Caco-2 cell model. The sequential relationship between the experimental permeability data and the degree of drug absorption in humans were established to verify the reliability of the experimental model and evaluate the Papp for the bidirectional transport of LH. Finally, the permeability of LH and model drugs was compared and the permeability of LH was evaluated based on the results of the two methods. BCS classification of the drug was determined in combination with the solubility of the drug in pH 1.0-pH 8.0 buffer solution. Results: The effective permeability measured in FeSSIF, FaSSIF and phosphate buffer in the PAMPA test were 1.82×10-6 cm·s-1, 27.7×10-6 cm·s-1 and 156×10-6 cm·s-1 for LH and 5.87×10-6 cm·s-1, 53.3×10-6 cm·s-1 and 134×10-6 cm·s-1 for metoprolol tartrate; The Papp(A-B) of nadolol, metoprolol tartrate, and digoxin were 0.795×10-6 cm·s-1, 15.1×10-6 cm·s-1 and 0.057 5×10-6 cm·s-1, the Papp(B-A) of digoxin were 10.5×10-6 cm·s-1. The efflux rate of digoxin is 192,the fluorescence yellow transmittance test was less than 1.0%, Papp for the three model drugs in the Caco-2 cell assay demonstrated that the cell model meets the requirements for characterizing drug permeability. The measured Papp(A-B) and Papp(B-A) of LH were 1.26×10-6 cm·s-1 and 22.8×10-6 cm·s-1; solubility of LH was 0.5 mg·mL-1-12.2 mg·mL-1. Conclusion: The Pe of LH in PAMPA is close to metoprolol tartrate in all three media, showing “high permeability”. However, the Papp (A-B) of LH in cell test is slightly higher than that of hypotonic nadolol and much lower than that of hypertonic metoprolol tartrate, which is close to that of moderately permeable atenolol (1.01×10-6 cm·s-1) reported in literature, showing “moderate permeability”, and the efflux rate (ER) is 18. This indicates that the absorption of LH in vivo may be affected by efflux transporters, so Caco-2 test results should prevail. The result of dividing the maximum individual dose (10 mg) by the minimum solubility(0.5 mg·mL-1) of the formulation is less than 250 mL, which is considered “highly soluble”. Therefore, LH is a “highly soluble, moderately permeable” drug, between BCS Class I and BCS Class Ⅲ.
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