Comparative Evaluation of Dehydroepiandrosterone Sulfate Potential to Predict Hepatic Organic Anion Transporting Polypeptide Transporter-Based Drug-Drug Interactions

Nishizawa, Kei; Nakanishi, Takeo; Tamai, Ikumi

doi:10.1124/dmd.116.072355

Cited by 4 publications

(3 citation statements)

References 21 publications

(27 reference statements)

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“…Based on studies in cynomolgus monkeys and in rats, DHEAS was suggested as potential endogenous probe for the prediction of drug-drug interactions mediated by inhibition of hepatic OATPs (Watanabe et al, 2015a;Nishizawa et al, 2017). DHEAS serum concentrations depend on sex with significantly higher concentrations in men than in women at ages 20-69 years and strongly depend on age (Orentreich et al, 1984).…”

Section: Biomarkers For Assessment Of Transporter Functionmentioning

confidence: 99%

Biomarkers for In Vivo Assessment of Transporter Function

Müller¹,

Sharma²,

König³

et al. 2018

Pharmacol Rev

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Drug-drug interactions are a major concern not only during clinical practice, but also in drug development. Due to limitations of in vitro-in vivo predictions of transporter-mediated drug-drug interactions, multiple clinical Phase I drug-drug interaction studies may become necessary for a new molecular entity to assess potential drug interaction liabilities. This is a resource-intensive process and exposes study participants, who frequently are healthy volunteers without benefit from study treatment, to the potential risks of a new drug in development. Therefore, there is currently a major interest in new approaches for better prediction of transporter-mediated drug-drug interactions. In particular, researchers in the field attempt to identify endogenous compounds as biomarkers for transporter function, such as hexadecanedioate, tetradecanedioate, coproporphyrins I and III, or glycochenodeoxycholate sulfate for hepatic uptake via organic anion transporting polypeptide 1B or N-methylnicotinamide for multidrug and toxin extrusion protein-mediated renal secretion. We summarize in this review the currently proposed biomarkers and potential limitations of the substances identified to date. Moreover, we suggest criteria based on current experiences, which may be used to assess the suitability of a biomarker for transporter function. Finally, further alternatives and supplemental approaches to classic drug-drug interaction studies are discussed.

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Section: Biomarkers For Assessment Of Transporter Functionmentioning

confidence: 99%

Biomarkers for In Vivo Assessment of Transporter Function

Müller¹,

Sharma²,

König³

et al. 2018

Pharmacol Rev

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show abstract

“…However, the biliary excretion clearance relative to liver exposure was unchanged, suggesting that increased plasma exposure of DHEAS by rifampin is primarily attributed to inhibition of hepatic Oatps. 70 Watanabe et al 71 evaluated DHEAS as an endogenous probe for inhibition of OATP1B using cynomolgus monkey. Active uptake of DHEAS was observed in both human and cynomolgus monkey hepatocytes, and this uptake was inhibited by rifampin.…”

Section: Dehydroepiandrosterone Sulfatementioning

confidence: 99%

Identification of Endogenous Biomarkers to Predict the Propensity of Drug Candidates to Cause Hepatic or Renal Transporter-Mediated Drug-Drug Interactions

Chu

Chan

Evers

2017

Journal of Pharmaceutical Sciences

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Drug transporters expressed in liver and kidney play a critical role in the elimination of a wide range of drugs and xenobiotics and inhibition of these transporters may therefore cause clinically significant drug-drug interactions (DDIs). Currently, in vitro transporter inhibition data are used to assess the risk that a drug candidate may act as an inhibitor of a transporter in patients at clinically relevant exposures. However, this approach is hampered by low confidence in in vitro to in vivo extrapolations, and large inter-system and inter-laboratory variability in in vitro data. Several endogenous compounds have been identified as substrates of drug transporters. Determining the impact of perpetrator drugs on the plasma or urinary exposure of these potential endogenous biomarkers in humans is being explored as an alternative approach to assess the DDI liability of drug candidates, especially in early drug development. In this review, we provide an overview of recently identified biomarkers used to study the inhibition of hepatic and renal transporters; summarize the methods and strategies employed to identify biomarkers; and discuss the utility, limitation, and future direction of biomarker approaches to predict transporter-mediated DDIs.

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“…Here, they are responsible for cellular uptake as a prerequisite for hepatic metabolism and elimination. In turn, the expression and function of these transporters affect systemic DHEAS levels as shown by enhanced DHEAS levels in monkeys and rats after treatment with the unspecific OATP inhibitor rifampicin ( Watanabe et al, 2015 ; Nishizawa et al, 2017 ). Assuming a DHEAS transport/uptake from the blood into the brain/CSF ( Kancheva et al, 2010 ), changes in DHEAS plasma concentration might indirectly influence the concentration in these compartments.…”

Section: Transporters That May Play a Role In The Transport Of Neurosmentioning

confidence: 99%

Neurosteroid Transport in the Brain: Role of ABC and SLC Transporters

2018

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Neurosteroids, comprising pregnane, androstane, and sulfated steroids can alter neuronal excitability through interaction with ligand-gated ion channels and other receptors and have therefore a therapeutic potential in several brain disorders. They can be formed in brain cells or are synthesized by an endocrine gland and reach the brain by penetrating the blood–brain barrier (BBB). Especially sulfated steroids such as pregnenolone sulfate (PregS) and dehydroepiandrosterone sulfate (DHEAS) depend on transporter proteins to cross membranes. In this review, we discuss the involvement of ATP-binding cassette (ABC)- and solute carrier (SLC)-type membrane proteins in the transport of these compounds at the BBB and in the choroid plexus (CP), but also in the secretion from neurons and glial cells. Among the ABC transporters, especially BCRP (ABCG2) and several MRP/ABCC subfamily members (MRP1, MRP4, MRP8) are expressed in the brain and known to efflux conjugated steroids. Furthermore, several SLC transporters have been shown to mediate cellular uptake of steroid sulfates. These include members of the OATP/SLCO subfamily, namely OATP1A2 and OATP2B1, as well as OAT3 (SLC22A3), which have been reported to be expressed at the BBB, in the CP and in part in neurons. Furthermore, a role of the organic solute transporter OSTα-OSTβ (SLC51A/B) in brain DHEAS/PregS homeostasis has been proposed. This transporter was reported to be localized especially in steroidogenic cells of the cerebellum and hippocampus. To date, the impact of transporters on neurosteroid homeostasis is still poorly understood. Further insights are desirable also with regard to the therapeutic potential of these compounds.

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Comparative Evaluation of Dehydroepiandrosterone Sulfate Potential to Predict Hepatic Organic Anion Transporting Polypeptide Transporter-Based Drug-Drug Interactions

Cited by 4 publications

References 21 publications

Biomarkers for In Vivo Assessment of Transporter Function

Biomarkers for In Vivo Assessment of Transporter Function

Identification of Endogenous Biomarkers to Predict the Propensity of Drug Candidates to Cause Hepatic or Renal Transporter-Mediated Drug-Drug Interactions

Neurosteroid Transport in the Brain: Role of ABC and SLC Transporters

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