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4.3.2 Ontogeny

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Identification of the specific proteins mediating organic anion secretion at the molecular level has allowed for the analysis of the pre‐ and postnatal ontogeny of the OATs. This is generally believed to have clinical implications for the dosing of drugs to premature infants and full‐term newborns, as well as children [63].

Initially, examinations revealed remarkably similar spatiotemporal expression patterns during murine kidney development with the mRNA encoding Slc22a6, Slc22a7, and Slc22a8 becoming detectable in late embryogenesis [32, 35, 64]. Employing organ culture models of nephrogenesis, the patterns of transporter expression and function were found to closely resemble those observed in vivo [64]. The approximately co‐temporal expression of these transporters in the developing proximal tubule of the kidney suggests the existence of a common transcriptional regulatory pathway for expression of the Oats [35].

Analyses of the maturation of these transporters after birth showed that Oat expression in the postnatal kidney increased postnatally in rodents with the highest level detectable in the adult [63]. A comprehensive analysis of the expression of the Slc and Abc transporters through all stages of rodent kidney development (i.e., embryonic, postnatal, and mature) from existing transcriptomic data sets revealed increases between the postnatal and mature stages of renal development [65]. Importantly, Slc22a6 and Slc22a8 were significantly upregulated in the maturing proximal tubule. In vivo studies also revealed a 4‐fold increase in the clearance of para‐aminohippurate (PAH, a classic Oat1 substrate), during postnatal development. A recent human study of OAT function reveals a roughly similar pattern of postnatal PAH handling [66].

The findings described above not only indicate that the OATs are functionally expressed during early proximal tubule differentiation and development; they also highlight the importance of studying postnatal expression and functional maturation. Given the increasingly lower gestational ages at which infants are being delivered, these types of studies likely have clinical implications for the dosing of drugs to premature infants and full‐term newborns, as well as children [63]. Furthermore, given that the gut–liver–kidney axis needs to become functionally efficient after birth, it has been argued that there must be coordinated regulation of these transporters [67].

Drug Transporters

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