Читать книгу Drug Transporters - Группа авторов - Страница 74

To understand physiologic and pharmacologic systems, it is critical to identify all of the components or proteins involved in those systems. The last few decades have ushered in a new understanding of the physiologic and pharmacologic roles of important zwitterions and organic cations, as the transporters involved in their absorption and disposition have been identified. It is now clear that transporters in the SLC22 family along with a few other transporters play key roles as determinants of systemic and tissue levels of cationic and zwitterionic drugs. At all levels from molecular to physiologic and pathophysiologic, there are major gaps in our knowledge. First and foremost, transporters for organic cations and zwitterions need to be discovered. With the recent deorphaning of SLC22A15, a key zwitterion transporter was identified in the human genome; however, many transporters remain orphans in the SLC superfamily and, in particular, in the SLC22 family. These transporters need to be deorphaned. Further, no transporter in the SLC22 family has been crystallized; therefore, the precise molecular transport mechanism is not known. Moreover, though many associations have been reproducibly observed between genetic variants in organic cation and zwitterion transporters and various clinical phenotypes, the mechanisms by which the transporter contributes to the phenotypes remain poorly understood. Rare variants in the transporters such as in SLC22A5 (OCTN2) are associated with fatal diseases, yet the function of these variants remain unknown and therapies remain poor at best. Finally, the physiologic, pharmacologic, and pathophysiologic systems that include these transporters need to be fully understood in order to obtain a full understanding of human biology and pharmacology.