Effects Of Crystal-form Modification On The Pharmacokinetics & Tissue Distribution Of Polymorphic Nimodipine In Rats After Oral Delivery

Previous studies have shown that the oral absorption and bioavailability of polymorphic drugs were affected by the crystalforms modification.However,plasma drug concentration could not directly influence the clinical efficacy of the drug which only exerts pharmacological activities after specific binding with the receptor or tissue.Consequently,the investigation about the effect of crysalforms modification of polymorphic drugs on in-vivo index after oral administration,which is higher than plasma drug concentration,is not only of theoretical significance for further revealing the relationship between crystalforms and curative effect,but also practical for dosage form design and rational clinical application.Quantitative determination of Nimodipine in plasma and tissues with HPLC method was established with Nitrendipine as a internal standard.With healthy rats and diabetic rats as research subjects,drug concentrations of plasma and tissues of heart,liver,spleen,lung,kidney and concentration variations over time were investigated at 1h,3h and 6h after oral administration of the two different crystal-forms as powder.The drug concentration ratio of tissue-to-plasma(Kt/p)was used as a criterion to evaluate the effect of diabetes mellitus on the in-vivo distribution of H-form and L-form.Following oral administarion by healthy rats,the significant difference of the two crystal-forms existed in heart(H:L=1.77),liver(L:H=4.86),spleen(H:L=2.37)and kidney(H:L=2.28)at 1h.The reason was attributed to the differences of absorption,first pass effect and plasma protein binding ratio of the two crystal-forms.The significant difference in plasma(L:H=4),heart(L:H=2.05)and liver(L:H=4.31)at 3h was resulted from the affinity discrepancies of the two crystal-forms to various tissues.The significant difference in heart(L:H=2.92)at 6h was related with the metabolism differences of the two crystal-forms.Following oral administarion by diabtic rats,the significant difference of the two crystal-forms existed in heart(L:H=7.40),liver(L:H=9.49),spleen(L:H=3.04)at 1h.The reason was ascribed to the poor microvascular permeability,which resulted in the weak transfer of H-form to various tissues.The significant difference in plasma(L:H=4.89),heart(L:H=5.73),liver(L:H=80.30)and lung(L:H=14.14)at 3h was resulted from the affinity differences of the two crystal-forms to liver enzyme and tissues.The significant difference in plasma(L:H=3.26),heart(L:H=4.35)and spleen(L:H=4.02)at 6h was due to the metabolism differences of the two crystal-forms.Plasma concentration of H-form increased under the influence of diabetes mellitus,which resulted in the decrease of CYP3A4 activity and P-gp amounts.While,the decrement of Kt/p value was related to the weak transfer to H-from to various tissues.Plasma concentration of L-form increased under the influence of diabetes mellitus.While,the Kt/p value hardly altered.