Transporters as a determinant of drug clearance and tissue distribution

Shitara, Yoshihisa; Horie, Toshiharu; Sugiyama, Yuichi

doi:10.1016/j.ejps.2005.12.003

Cited by 456 publications

(319 citation statements)

References 125 publications

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“…Let us consider the impact of the function of metabolic enzymes and uptake transporters on the hepatic clearance of drugs from the pharmacokinetic theory. 16,17) As shown in Fig. 3 …”

Section: Oatp1b1 and Oatp1b3 As Determinants Of Hepatic Clearance Of mentioning

confidence: 99%

Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

Maeda

2015

Biological & Pharmaceutical Bulletin

115

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Nobody doubts the importance of organic anion transporting polypeptide (OATP)1B1 and 1B3 in the clinical pharmacokinetics of substrate drugs. Based on the theory of pharmacokinetics, even if a drug is eliminated from the body by extensive metabolism, the rate-determining process of the hepatic intrinsic clearance of OATP substrates is often hepatic uptake. Because of their broad substrate specificities, once the functions of OATP1B1 or OATP1B3 are altered by several kinds of special occasions such as drug-drug interactions (DDI) and genetic polymorphisms of transporter genes, the hepatic clearance of many kinds of structurally-unrelated drugs is expected to be changed. In some cases, these alterations of pharmacokinetics lead to modified pharmacological effects and adverse reactions such as statin-induced myotoxicity and the glucose-lowering effect of anti-diabetes drugs. Thus, appropriate methods with which to quantitatively predict the changes in plasma and tissue concentrations of drugs are needed in the process of drug development. As for DDI, a static model that takes into consideration of the theoretically-maximum unbound inhibitor concentration is often used for the sensitive detection of possible DDI risks and this method has been adopted in several regulatory guidance/guidelines on DDI. Regarding genetic polymorphisms, the effects of SLCO1B1 c.388A>G and c.521T>C on the pharmacokinetics of substrate drugs have been extensively investigated. Even though there are some discrepancies, c.521T>C generally decreased hepatic uptake activity, while c.388A>G tended to slightly increase it. This article briefly summarizes the current status of research on hepatic OATP1B1 and OATP1B3 and the clinical significance of their functions.

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“…Let us consider the impact of the function of metabolic enzymes and uptake transporters on the hepatic clearance of drugs from the pharmacokinetic theory. 16,17) As shown in Fig. 3 …”

Section: Oatp1b1 and Oatp1b3 As Determinants Of Hepatic Clearance Of mentioning

confidence: 99%

Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

Maeda

2015

Biological & Pharmaceutical Bulletin

115

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“…With one exception, they are mostly expressed in liver and/or kidney, the two principal excretory organs of the body [4][5][6]. The exception is Oat6, which is highly expressed in olfactory mucosa (with a lesser degree of expression in testis and early embryonic tissues) [7].…”

Section: Introductionmentioning

confidence: 99%

Olfactory mucosa-expressed organic anion transporter, Oat6, manifests high affinity interactions with odorant organic anions

Kaler

Truong

Sweeney

et al. 2006

Biochemical and Biophysical Research Communications

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We have characterized the expression of organic anion transporter 6, Oat6 (slc22a20), in olfactory mucosa, as well as its interaction with several odorant organic anions. In situ hybridization reveals diffuse Oat6 expression throughout olfactory epithelium, yet olfactory neurons laser-capture microdissected from either the main olfactory epithelium (MOE) or the vomeronasal organ (VNO) did not express Oat6 mRNA. These data suggest that Oat6 is expressed in non-neuronal cells of olfactory tissue, such as epithelial and/or other supporting cells. We next investigated interaction of Oat6 with several small organic anions that have previously been identified as odortype components in mouse urine. We find that each of these compounds, propionate, 2-and 3-methylbutyrate, benzoate, heptanoate and 2-ethylhexanoate, inhibits Oat6-mediated uptake of a labeled tracer, estrone sulfate, consistent with their being Oat6 substrates. Previously, we noted defects in the renal elimination of odortype and odortype-like molecules in Oat1 knockout mice. The finding that such molecules interact with Oat6 raises the possibility that odorants secreted into the urine through one OAT-mediated mechanism are transported through the olfactory mucosa through another OATmediated mechanism. Oat6 might play a direct or indirect role in olfaction, such as modulation of the availability of odorant organic anions at the mucosal surface for presentation to olfactory neurons or facilitation of delivery to a distal site of chemosensation, among other possibilities that we discuss.

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“…Our understanding of the importance of hepatic transporters in controlling the disposition of drugs continues to evolve (Shitara et al, 2006;Niemi, 2007;Funk, 2008;Giacomini et al, 2010). The activity of members of the solute carrier and ATP-binding cassette families of transporter proteins may provide a mechanistic explanation for the limited success achieved for some drugs using standard (hepatic microsomal) in vitro experiments to predict pharmacokinetic aspects of clearance and drug-drug interaction (DDI) potential (Lam et al, 2006;Soars et al, 2007;Parker and Houston, 2008).…”

Section: Introductionmentioning

confidence: 99%

Comparative Use of Isolated Hepatocytes and Hepatic Microsomes for Cytochrome P450 Inhibition Studies: Transporter-Enzyme Interplay

Brown¹,

Wilby²,

Alder³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Accurate assignment of the concentration of victim drug/inhibitor available at the enzyme active site, both in vivo and within an in vitro incubation, is an essential requirement in rationalizing and predicting drug-drug interactions. Inhibitor accumulation within the liver, whether as a result of active transport processes or intracellular binding, may best be accounted for using hepatocytes rather than hepatic microsomes to estimate in vitro inhibitory potency. The aims of this study were to compare K i values determined in rat liver microsomes and freshly isolated rat hepatocytes of four cytochrome P450 (P450) inhibitors (clarithromycin, enoxacin, nelfinavir, and saquinavir) with known hepatic transporter involvement and a range of uptake (cell/medium concentration ratios 20-3000) and clearance (10-1200 l/min/10 6 cells) properties.Inhibition studies were performed using two well established P450 probe substrates (theophylline and midazolam). Comparison of unbound K i values showed marked differences between the two in vitro systems for inhibition of metabolism. In two cases (clarithromycin and enoxacin, both low-clearance drugs), inhibitory potency in hepatocytes markedly exceeded that in microsomes (10-to 20-fold), and this result was consistent with their high cell/medium concentration ratios. For nelfinavir and saquinavir (high-clearance, extensively metabolized drugs), the opposite trend was seen in the K i values: despite very high cell/medium concentration ratios, stronger inhibition was evident within microsomal preparations. Hence, the consequences of hepatic accumulation resulting from uptake transporters vary according to the clearance of the inhibitor. This study demonstrates that transporter-enzyme interplay can result in differences in inhibitory potency between microsomes and hepatocytes and hence drug-drug interaction predictions that are not always intuitive.

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Transporters as a determinant of drug clearance and tissue distribution

Cited by 456 publications

References 125 publications

Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

Olfactory mucosa-expressed organic anion transporter, Oat6, manifests high affinity interactions with odorant organic anions

Comparative Use of Isolated Hepatocytes and Hepatic Microsomes for Cytochrome P450 Inhibition Studies: Transporter-Enzyme Interplay

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