Karelle Ménochet's research while affiliated with Manchester University and other places

Publications (13)

Article
• The use of hepatocytes to predict human hepatic metabolic clearance is the gold standard approach. However, whilst enzymes are well characterised, knowledge gaps remain for transporters. Furthermore, methods to study specific transporter involvement are often complicated by overlapping substrate specificity. Selective substrates and inhibitors wo...
Chapter
This chapter focuses on factors influencing regional epithelial permeation of drugs related especially to transporters. It highlights the important key messages as regard to modified‐release formulations. Drug absorption for ionizable drugs is determined by the pH in the region of intended release. Uptake and efflux transporters expressed in the ga...
Article
Full-text available
Coproporphyrin I (CPI) is an endogenous biomarker of organic anion transporting polypeptides 1B (OATP1B) activity and associated drug‐drug interactions. In this study, a minimal physiologically‐based pharmacokinetic model was developed to investigate the impact of OATP1B1 genotype (c.521T>C), ethnicity, and sex on CPI pharmacokinetics and inter‐ind...
Article
Full-text available
• Determine the inhibition mechanism through which cyclosporine inhibits the uptake and metabolism of atorvastatin in fresh rat hepatocytes using mechanistic models applied to data generated using a high throughput oil spin method. • Atorvastatin was incubated in fresh rat hepatocytes (0.05–150 nmol/ml) with or without 20 min pre-incubation with 10...
Article
Endogenous biomarkers can be clinically relevant tools for the assessment of transporter function in vivo and corresponding drug-drug interactions (DDIs). The aim of this study was to perform systematic evaluation of plasma data obtained for 20 endogenous molecules in the same healthy subjects (n 5 8-12) in the absence and presence of organic anion...
Article
Full-text available
This study evaluates coproporphyrin I (CPI) as a selective endogenous biomarker of OATP1B-mediated drug-drug interactions (DDIs) relative to clinical probe rosuvastatin using nonlinear mixed-effect modelling. Plasma and urine CPI data in the presence/absence of rifampicin were modelled to describe CPI synthesis, elimination clearances and obtain ri...
Article
Interindividual variability in activity of uptake transporters is evident in vivo, yet limited data exist in vitro, confounding in vitro-in vivo extrapolation. The uptake kinetics of seven organic anion-transporting polypeptide substrates was investigated over a concentration range in plated cryopreserved human hepatocytes. Active uptake clearance...
Article
Kinetic parameters describing hepatic uptake in hepatocytes are frequently estimated without appropriate incorporation of bidirectional passive diffusion, intracellular binding, and metabolism. A mechanistic two-compartment model was developed to describe all of the processes occurring during the in vitro uptake experiments performed in freshly iso...
Article
Identifying any extrahepatic excretion phenomenon in preclinical species is crucial for an accurate prediction of the pharmacokinetics in man. This understanding is particularly key for drugs with a small volume of distribution, because they require an especially low total clearance to be suitable for a once-a-day dosing regimen in man. In this stu...
Article
In silico models that predict the rate of human renal clearance for a diverse set of drugs, that exhibit both active secretion and net re-absorption, have been produced using three statistical approaches. Partial Least Squares (PLS) and Random Forests (RF) have been used to produce continuous models whereas Classification And Regression Trees (CART...

Citations

... In terms of its canonical role in drug metabolism, PXR was discovered in 1998 (Bertilsson, Heidrich et al. 1998, Blumberg and Evans 1998, Kliewer, Moore et al. 1998) and described as a master regulator of drug metabolism in that PXR can enhance the clearance of its own xenobiotic ligands via enzymatic (Phase I & II ) and transporter-mediated (Phase III transporters) effects. In. addition, PXR is an important mediator of drug-drug interactions when multiple drugs are co-administered (Goodwin, Hodgson et al. 1999, Wang, Dai et al. 2014, Shehu, Li et al. 2016, Nicolussi, Drewe et al. 2020, Wang, Bwayi et al. 2020, Hall, Chanteux et al. 2021. PXR also has a role in bile acid metabolism, acting on feedback and feed-forward mechanisms to alter bile acid production from cholesterol (Handschin and Meyer 2005). ...
... The accurate prediction of pDDIs can be complex as they may be affected by the concomitant presence of confounding factors, such as patients' characteristics (i.e., ageing, gender, etc.), drug-induced physiological alterations (i.e., changes in hepatic blood flow, alterations in the protein binding, etc.), ICU-induced pathological alterations (i.e., hypoalbuminemia, augmented renal clearance, etc.), and/or complex dialytic procedures that can significantly impact in the processes of antibiotic distribution, metabolism, and/or elimination, ultimately affecting the clinical relevance of pDDIs, although not specifically in the ICU setting. More recently, some effects of the ethnicity/genetic background, as well as of COVID-19, on drug pharmacokinetics and pDDIs have been also documented [80,81]. ...
... Dynamical metabolic models have been applied in various contexts. Recurrently pursued objectives are 1) understanding dynamical processes [15,16], for example, through comparison of competing models [17]; 2) inferring control mechanisms and rate-limiting steps [13,18]; and 3) leveraging those to push some system of interest in specific directions, for example, for strain optimization or drug target identification) [14,19,20]. ...
... However, such approaches may yield relatively high false-positive rates. Even for true-positive rates, it is difficult to predict the magnitude of the potential DDIs. 5 Various endogenous OATP1B substrates have been proposed as surrogate probes [5][6][7] to facilitate the risk assessment of pharmacokinetic DDIs in early clinical phases. Among them, the heme synthesis by-product, coproporphyrin I (CP-I), [8][9][10] has been used as biomarkers for assessing OATP1B-mediated DDIs. ...
... Consequently, the pharmaceutical industry is beginning to use CP-I in combination with other OATP1B-DDI biomarkers in setting exclusion criteria for drug candidates with high DDI risk, guiding decisions regarding the conduct of clinical DDI studies, and designing phase III trials with a minimum risk of DDI. 19 Modeling and simulation approaches to describe blood concentration-time profiles of CP-I in the absence and presence of OATP inhibitors have been reported using empirical compartment models 20,21 and physiologicallybased pharmacokinetic (PBPK) models. 22,23 In our previous study, three unknown PBPK parameters including the hepatic overall intrinsic clearance (CL int,all ), the biosynthesis rate of CP-I (v syn ), and the hepatic OATP1B RIF inhibition constant (K i,u,OATP ) were estimated using a conventional fitting approach and a nonlinear least-squares algorithm. ...
... In other words, the two species differed by almost an order of magnitude. These results were broadly anticipated, based on several reports on the uptake rates of OATP-substrates in rat liver versus the corresponding observations in humans [38][39][40]. One explanation for such a large difference could be different affinities for gadoxetate in humans and rats, since the OATP1B1/B3 transporters are not represented by undisputed orthologs in rats [38,41]. ...
... 36 Uptake experiments were performed at 37°C with duplicate incubations per condition, as previously described. 35 Uptake of gadoxetate (Primovist injection solution, Bayer, Germany) was evaluated following incubation (0.5−150 min) at nominal media concentrations of 0.01−10 mM. Extended incubation timepoints (up to 150 min) were selected based on previous publications 35 and existing in-house data to enable characterization of the steady-state intracellular concentration. ...
... The developed PBPK/PD models for the MDM2 inhibitor siremadlin and the MEK inhibitor trametinib were able to describe both the pharmacokinetic and pharmacodynamic profiles of these drugs. The models consider the oral (p.o.) administration of siremadlin and trametinib, the first-order absorption mechanism, a full-body distribution model, hepatic metabolism and renal excretion for siremadlin (renal excretion calculated using the FCIM method [38]), intravenous clearance for trametinib, and a permeabilitylimited tumour distribution model. ...
... This figure was adapted based on Lu et al. (2021a) with permission from the publisher. CHOU AND LIN | 3 2021; Jia et al., 2020;Kosugi and Hosea, 2020;Liu et al., 2005;Niwa, 2003;Paine et al., 2010;Paixao et al., 2010;Sarigiannis et al., 2017;Shen et al., 2010;Talevi et al., 2011;Wambaugh et al., 2015;Wang et al., 2017;Yun et al., 2014;Zhang et al., 2008). These ADME parameters can then be incorporated into a generic PBPK model (Wambaugh et al., 2015). ...