Development of mechanisms for drug excretion

Hook, Jerry B.; Hewitt, William R.

doi:10.1016/0002-9343(77)90404-1

Cited by 53 publications

(26 citation statements)

References 67 publications

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“…This is paralleled by functional changes, such as increasing PAH clearance (96). There is evidence in animals for a developmental inducibility window, during which renal drug transporters may, during the early postnatal period, be induced by substrates or by hormones (97,98). If this is true in humans, substrate induction could theoretically enhance the ability of a premature infant's kidney to excrete potentially deleterious drugs and toxins.…”

Section: Pediatric Developmental Pharmacology and Drug Elimination Inmentioning

confidence: 99%

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Nigám¹,

Wu²,

Bush³

et al. 2015

Clinical Journal of the American Society of Nephrology

221

192

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The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liverderived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.

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Section: Pediatric Developmental Pharmacology and Drug Elimination Inmentioning

confidence: 99%

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Nigám¹,

Wu²,

Bush³

et al. 2015

Clinical Journal of the American Society of Nephrology

221

192

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show abstract

“…In children, certain differences in kidney function, e.g., the glomerular filtration of inulin (41) and the excretion of antibiotics (42), can clearly be attributed to kidney maturation on an anatomical level, e.g., length and number of nephrons. However, other differences, e.g., the increased clearance of digoxin in young children, cannot be explained solely by these anatomical changes (43)(44)(45). In such cases, transporters are likely to play a crucial role; however, the underlying molecular processes for differences in renal clearance are poorly understood in a developmental context.…”

Section: Wwwannualreviewsorg • Renal Drug Transporters 521mentioning

confidence: 99%

“…In humans, MDR1 mRNA is detected in the kidney by 7 weeks of gestation, and its tissue distribution pattern differs from that seen in adult tissues (47). In addition, a disproportional increase in organic anion secretion relative to kidney mass has been reported in human subjects, suggesting a specific maturation of the organic anion transport system during development (43). Interestingly, cephalosporin-related nephrotoxicity occurs more frequently in adults than in children (48,49).…”

Section: Wwwannualreviewsorg • Renal Drug Transporters 521mentioning

confidence: 99%

Renal Transporters in Drug Development

Morrissey

Stocker

Wittwer

et al. 2013

Annu. Rev. Pharmacol. Toxicol.

280

277

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The kidney plays a vital role in the body's defense against potentially toxic xenobiotics and metabolic waste products through elimination pathways. In particular, secretory transporters in the proximal tubule are major determinants of the disposition of xenobiotics, including many prescription drugs. In the past decade, considerable progress has been made in understanding the impact of renal transporters on the disposition of many clinically used drugs. In addition, renal transporters have been implicated as sites for numerous clinically important drug-drug interactions. This review begins with a description of renal drug handling and presents relevant equations for the calculation of renal clearance, including filtration and secretory clearance. In addition, data on the localization, expression, substrates, and inhibitors of renal drug transporters are tabulated. The recent US Food and Drug Administration drug-drug interaction draft guidance as it pertains to the study of renal drug transporters is presented. Renal drug elimination in special populations and transporter splicing variants are also described.

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Section: Ontogeny and Morphogenesismentioning

confidence: 99%

“…Transport is relatively low at birth, then increases sharply over the first few weeks of neonatal life, before declining to adult levels (Barnett et al, 1949;Horster and Lewy, 1970;Kim et al, 1972;Hook and Hewitt, 1977). This neonatal increase seems to be specifically caused by the maturation of the transport system rather than by the growth and development of the kidney (Hook and Hewitt, 1977). Interestingly, OA transport is inducible by substrate during a limited period that roughly coincides with the phase of postnatal maturation Hook, 1969, 1970;Stopp et al, 1978), suggesting that similar mechanisms might be involved in both these processes.…”

Section: Ontogeny and Morphogenesismentioning

confidence: 99%

The Molecular Pharmacology of Organic Anion Transporters: from DNA to FDA?

Eraly¹,

Bush²,

Sampogna³

et al. 2004

Mol Pharmacol

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Renal organic anion secretion has been implicated in numerous clinically significant drug interactions and adverse reactions, indicating the importance of a detailed understanding of this pathway for the development of optimum therapeutics. With the cloning of multiple genes encoding organic anion transporters (OATs), the study of organic anion secretion has entered the molecular age. In this review, we focus on various aspects of the molecular biology and pharmacology of the OATs, including discussion of their structural biology, genomic organization in pairs, developmental regulation, toxicology, and pharmacogenetics. We propose functional, pathophysiological, and evolutionary hypotheses to help explain recent experimental and genomic data.

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Development of mechanisms for drug excretion

Cited by 53 publications

References 67 publications

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Renal Transporters in Drug Development

The Molecular Pharmacology of Organic Anion Transporters: from DNA to FDA?

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