Use of<i>in vitro</i>transporter assays to understand hepatic and renal disposition of new drug candidates

Sahi, Jasminder

doi:10.1517/17425255.1.3.409

Cited by 24 publications

(19 citation statements)

References 191 publications

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“…Thus, the in vivo excreta results showed that degarelix is mainly excreted unchanged via the urine and is subject to extensive sequential peptidic degradation during its elimination via the hepato-biliary pathway. The results are in line with data for other compounds of similar size and structure as degarelix and in line with the fact that compounds of this size (molecular weight, 1632 Da) are more likely to be eliminated by the hepato-biliary pathway (Sahi, 2005).…”

Section: Discussionsupporting

confidence: 87%

“…Because degarelix has been shown not to induce CYP3A4 in vitro, no further tests of P-glycoprotein induction , our data show that degarelix is highly unlikely to cause any drug interaction with coadministrated drugs when used for the treatment of patients with prostate cancer. Similar to other peptide drugs of this size (Sahi, 2005), degarelix is subject to proteolysis by endopeptidases, and unchanged degarelix and its metabolites are fully excreted via the hepatic and urinary pathway. Therefore, systemic exposure to any metabolic products also seems to be low and/or negligible.…”

Section: Discussionmentioning

confidence: 99%

“…Hepatic and renal transporters play a key role in drug clearance and can contribute to drug-drug interactions and toxicity (Glavinas et al, 2004;Sahi, 2005). Mass balance studies of degarelix in rat, dog, and monkey have shown that 50% of total administrated radioactivity was excreted via the hepatic pathways, and the majority of the radioactivity excreted in the bile was truncated metabolites of degarelix.…”

Section: Introductionmentioning

confidence: 99%

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In Vitro and In Vivo Human Metabolism of Degarelix, a Gonadotropin-Releasing Hormone Receptor Blocker

Sonesson

Rasmussen

2013

Drug Metab Dispos

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Degarelix is a decapeptide that shows high affinity/selectivity to human gonadotropin-releasing hormone receptors and has been approved for the treatment of advanced prostate cancer in the United States, European Union, and Japan. To investigate the metabolism of degarelix in humans, in vitro metabolism was addressed in liver tissue and in vivo metabolism was studied in plasma and excreta samples collected in clinical studies. In addition, drug transporter interaction potential of degarelix with selected efflux transporters and uptake transporters was studied using in vitro membrane vesicle-based assays and whole cell-based assays. In vitro degradation was observed in fresh hepatocytes; less than 25% of the initial concentration of degarelix remained after incubation at 37°C for 2 hours. One metabolite was detected, representing a truncated nonapeptide of degarelix. The same metabolite was also detected at low concentrations in plasma. The in vivo investigations also showed that degarelix is excreted unchanged via the urine but is undergoing extensive sequential peptidic degradation during its elimination via the hepato-biliary pathway. No unique human metabolites of degarelix were detected in the circulation or in the excreta. Degarelix did not show any interaction with selected efflux transporters and uptake transporters up to concentrations representing 200 times the clinical concentration. Because degarelix does not seem to interact with the cytochrome P450 enzyme system as substrate, inhibitor, or inducer and does not show any interaction with hepatic and renal uptake and efflux transporters, the risk for pharmacokinetic drug-drug interactions with this compound is highly unlikely.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In Vitro and In Vivo Human Metabolism of Degarelix, a Gonadotropin-Releasing Hormone Receptor Blocker

Sonesson

Rasmussen

2013

Drug Metab Dispos

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“…Furthermore, the free fraction of drug in plasma and dose (in particular if Ͼ100 mg) are other important parameters to consider when evaluating the need for a clinical drug interaction study. As discussed in the FDA Guidance and in the review by Sahi (2005), drug-drug interaction potential can be estimated using [I]/K i , where I is inhibitor concentration and K i is the inhibition constant (note that use of total concentration is recommended in the FDA Guidance because this provides the most conservative estimate). If the [I]/K i ratio is Ͻ0.02, the chance of an interaction is remote.…”

Section: Discussionmentioning

confidence: 99%

In Vitro P-Glycoprotein Inhibition Assays for Assessment of Clinical Drug Interaction Potential of New Drug Candidates: A Recommendation for Probe Substrates

Rautio¹,

Humphreys²,

Webster³

et al. 2006

Drug Metab Dispos

245

223

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ABSTRACT:Because modulation of P-glycoprotein (Pgp) through inhibition or induction can lead to drug-drug interactions by altering intestinal, central nervous system, renal, or biliary efflux, it is anticipated that information regarding the potential interaction of drug candidates with Pgp will be a future regulatory expectation. Therefore, to be able to utilize in vitro Pgp inhibition findings to guide clinical drug interaction studies, the utility of five probe substrates (calcein-AM, colchicine, digoxin, prazosin, and vinblastine) was evaluated by inhibiting their Pgp-mediated transport across multidrug resistance-1-transfected Madin-Darby canine kidney cell type II monolayers with 20 diverse drugs having various degrees of Pgp interaction (e.g., efflux ratio, ATPase, and calcein-AM inhibition). Overall, the rank order of inhibition was generally similar with IC 50 values typically within 3-to 5-fold of each other. However, several notable differences in the IC 50 values were observed. Digoxin and prazosin were the most sensitive probes (e.g., lowest IC 50 values), followed by colchicine, vinblastine, and calcein-AM. Inclusion of other considerations such as a large dynamic range, commercially available radiolabel, and a clinically meaningful probe makes digoxin an attractive probe substrate. Therefore, it is recommended that digoxin be considered as the standard in vitro probe to investigate the inhibition profiles of new drug candidates. Furthermore, this study shows that it may not be necessary to generate IC 50 values with multiple probe substrates for Pgp as is currently done for cytochrome P450 3A4. Finally, a strategy integrating results from in vitro assays (efflux, inhibition, and ATPase) is provided to further guide clinical interaction studies.P-glycoprotein (Pgp) is a member of the ATP-binding cassette superfamily of transport proteins and is expressed in numerous tissues such as the luminal membrane of the small intestine and blood-brain barrier, and the apical membranes of excretory organs such as liver and kidney (Ayrton and Morgan, 2001). Pgp has broad substrate recognition, which can affect the pharmacokinetics, efficacy, safety, and target organ specificity of drugs. As a result, drug-drug interactions resulting from inhibition or induction of Pgp are a recognized clinical concern (Englund et al., 2004;Balayssac et al., 2005) recently highlighted in the Food and Drug Administration (FDA) concept paper "Drug Interaction Studies-Study Design, Data Analysis, and Implications for Dosing and Labeling" (FDA, 2004).Despite many years of investigation, considerable uncertainty remains about the number of drug binding sites within Pgp and their mutual relationships. It is postulated that the transmembrane regions of Pgp form a large binding pocket (Sharom et al., 1998;Lugo and Sharom, 2005) composed of amino acid residues from multiple transmembrane segments Clarke, 2001, 2002). Recent experiments investigating drug binding (Martin et al., 2000), fluorescent dye uptake (Shapiro and Ling, 1997;Lugo ...

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“…There is evidence to suggest that AO contributes to the pharmacokinetic interaction between zaleplon and cimetidine (Renwick et al, 2002); however, cimetidine is known to inhibit P450 enzymes and renal organic anion and cation transporters (Somogyi, 1996;Sahi, 2005), so the specific contribution of AO to the observed DDI is not known. Recently, a group of scientists, under the auspices of the Drug Metabolism Leadership Group of the Innovation and Quality Consortium, conducted an evaluation of having a metabolite as the sole contributor to P450 inhibition-based DDIs.…”

Section: )mentioning

confidence: 99%

VX-509 (Decernotinib)-Mediated CYP3A Time-Dependent Inhibition: An Aldehyde Oxidase Metabolite as a Perpetrator of Drug-Drug Interactions

Zetterberg

Maltais

Laitinen

et al. 2016

Drug Metabolism and Disposition

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(R)-2-((2-(1H-pyrrolo [2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide decernotinib) is an oral Janus kinase 3 inhibitor that has been studied in patients with rheumatoid arthritis. Patients with rheumatoid arthritis often receive multiple medications, such as statins and steroids, to manage the signs and symptoms of comorbidities, which increases the chances of drug-drug interactions (DDIs). Mechanism-based inhibition is a subset of time-dependent inhibition (TDI) and occurs when a molecule forms a reactive metabolite which irreversibly binds and inactivates drug-metabolizing enzymes, potentially increasing the systemic load to toxic concentrations. Traditionally, perpetrating compounds are screened using human liver microsomes (HLMs); however, this system may be inadequate when the precipitant is activated by a non-cytochrome P450 (P450)-mediated pathway. Even though studies assessing competitive inhibition and TDI using HLM suggested a low risk for CYP3A4-mediated DDI in the clinic, VX-509 increased the area under the curve of midazolam, atorvastatin, and methyl-prednisolone by approximately 12.0-, 2.7-, and 4.3-fold, respectively. Metabolite identification studies using human liver cytosol indicated that VX-509 is converted to an oxidative metabolite, which is the perpetrator of the DDIs observed in the clinic. As opposed to HLM, hepatocytes contain the full complement of drug-metabolizing enzymes and transporters and can be used to assess TDI arising from non-P450-mediated metabolic pathways. In the current study, we highlight the role of aldehyde oxidase in the formation of the hydroxylmetabolite of VX-509, which is involved in clinically significant TDIbased DDIs and represents an additional example in which a system-dependent prediction of TDI would be evident.

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Use ofin vitrotransporter assays to understand hepatic and renal disposition of new drug candidates

Cited by 24 publications

References 191 publications

In Vitro and In Vivo Human Metabolism of Degarelix, a Gonadotropin-Releasing Hormone Receptor Blocker

In Vitro and In Vivo Human Metabolism of Degarelix, a Gonadotropin-Releasing Hormone Receptor Blocker

In Vitro P-Glycoprotein Inhibition Assays for Assessment of Clinical Drug Interaction Potential of New Drug Candidates: A Recommendation for Probe Substrates

VX-509 (Decernotinib)-Mediated CYP3A Time-Dependent Inhibition: An Aldehyde Oxidase Metabolite as a Perpetrator of Drug-Drug Interactions

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