Consequences of Polymorphism

Interestingly, these assays have been employed to address the functional consequences of polymorphisms in the ABCC family of transporters but no notable alterations in transport capacity have been found (43). It seems that although ABCC transporters contain several potentially important polymorphisms and are important in drug transport overall, functional variability is actually quite low. This is perhaps the reason for the multiple negative studies that have assessed ABCC polymorphisms as they relate to drug bioavailability (20). 

Alvan G. Clinical consequences of polymorphic drug oxidation. Fund Clin Pharmacol 1991 5 209. Alvan G. Genetic polymorphisms in drug metabolism. J Internal Med 1992 231 571. 

The consequences of polymorphisms of drug response depend on a further number of contributing factors [10] (1) at which point on the concentration-effect rela-... 

In the interim a great deal has been learnt about the nature and consequences of polymorphism, but the fact that over sixty years later both of these questions are still largely unanswered is a challenge to chemists, physicists, and crystallographers. What has been learnt is the subject of the remainder of this book and is meant to provide a jumping-off point for the investigation of these questions. 

The most important consequence of polymorphism is the possible difference in the bioavailability of different polymorphic forms of a dmg particularly when the dmg is poorly soluble. The rate of absorption of such a dmg is often dependent upon its rate of dissolution. The most stable polymorph usually has the lowest solubility and often the slowest dissolution rate. Fortunately, the difference in the bioavailability of different polymorphic forms of a dmg is usually insignificant. It has been proposed that when the free energy differences between the polymorphs are small there may be no significant differences in their biopharmaceutical behaviour as measured by the blood levels they achieve. Only when the differences are large may they affect the extent of absorption. For example, for... 

Spielberg SP. N-acetpltransferases pharmacogenetics and clinical consequences of polymorphic drug metabolism. J Pharmacoldnet Biopharm 1996 24 509-19. 

Drayer DE, Reidenberg MM. 1977. Clinical consequences of polymorphic acetylation . Clin. Pharmacol. Ther. 22 251-258. 

V. Consequences of Polymorphism and Solvate Formation on the Bioavailability of Drug Substances... 

These remarks serve to emphasise some of the more important practical implications and consequences of polymorphism. Overcoming the problems encountered requires a deeper understanding of the processes of nucleation, crystal growth and polymorphic transformation. Several recent studies relating to these topics are reviewed in the next section. 

Several 1,3-dialkylimidazolium halides have been intensely structurally investigated, not only as a consequence of polymorphism but also as subjects of studies of the dynamics of processes occurring during melting and crystallisation and associated butyl group conformer lability. These aspects have been introduced in Section 11.2. 

Furlong, C.E., Richter, R.J., Li, W.F, et al., 2008. The functional consequences of polymorphisms in the human PONl gene. In Mackness, B., Mackness, M., Aviram, M., Paragh, G. (Eds ), The Paraoxonases Their Role in Disease, Development and Xenobiotic Metabolism, Springer, Dordrecht, The Netherlands, pp. 267-281. 

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