Application of a Physiologically Based Pharmacokinetic Model to Assess Propofol Hepatic and Renal Glucuronidation in Isolation: Utility of In Vitro and In Vivo Data

Gill, Katherine L.; Gertz, Michael; Houston, J. Brian; Galetin, Aleksandra

doi:10.1124/dmd.112.050294

Cited by 26 publications

(21 citation statements)

References 67 publications

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“…These isoforms may also play an important role in the extrahepatic glucuronidation of bupropion, particularly in the kidney where UGT1A9 is the predominant isoform expressed (Margaillan et al, 2015a) and in the gut where UGT2B7 and UGT1A9 are present (Harbourt et al, 2012;Fallon et al, 2013). Further exploration of extrahepatic bupropion metabolism could more comprehensively describe bupropion metabolite disposition and facilitate quantitative in vitro-in vivo extrapolation of bupropion metabolite kinetics (Gill et al, 2012(Gill et al, , 2013.…”

Section: Discussionmentioning

confidence: 99%

Stereoselective Glucuronidation of Bupropion Metabolites In Vitro and In Vivo

Gufford

Metzger

et al. 2016

Drug Metabolism and Disposition

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Bupropion is a widely used antidepressant and smoking cessation aid in addition to being one of two US Food and Drug Administration-recommended probe substrates for evaluation of cytochrome P450 2B6 activity. Racemic bupropion undergoes oxidative and reductive metabolism, producing a complex profile of pharmacologically active metabolites with relatively little known about the mechanisms underlying their elimination. A liquid chromatography-tandem mass spectrometry assay was developed to simultaneously separate and detect glucuronide metabolites of (R,R)-and (S,S)-hydroxybupropion, (R,R)-and (S,S)-hydrobupropion (threo) and (S,R)-and (R,S)-hydrobupropion (erythro), in human urine and liver subcellular fractions to begin exploring mechanisms underlying enantioselective metabolism and elimination of bupropion metabolites. Human liver microsomal data revealed marked glucuronidation stereoselectivity [Cl int , 11.4 versus 4.3 ml/min per milligram for the formation of (R,R)-and (S,S)-hydroxybupropion glucuronide; and Cl max , 7.7 versus 1.1 ml/min per milligram for the formation of (R,R)-and (S,S)-hydrobupropion glucuronide], in concurrence with observed enantioselective urinary elimination of bupropion glucuronide conjugates. Approximately 10% of the administered bupropion dose was recovered in the urine as metabolites with glucuronide metabolites, accounting for approximately 40%, 15%, and 7% of the total excreted hydroxybupropion, erythrohydrobupropion, and threo-hydrobupropion, respectively. Elimination pathways were further characterized using an expressed UDP-glucuronosyl transferase (UGT) panel with bupropion enantiomers (both individual and racemic) as substrates. UGT2B7 catalyzed the stereoselective formation of glucuronides of hydroxybupropion, (S,S)-hydrobupropion, (S,R)-and (R,S)-hydrobupropion; UGT1A9 catalyzed the formation of (R,R)-hydrobupropion glucuronide. These data systematically describe the metabolic pathways underlying bupropion metabolite disposition and significantly expand our knowledge of potential contributors to the interindividual and intraindividual variability in therapeutic and toxic effects of bupropion in humans.

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Section: Discussionmentioning

confidence: 99%

Stereoselective Glucuronidation of Bupropion Metabolites In Vitro and In Vivo

Gufford

Metzger

et al. 2016

Drug Metabolism and Disposition

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“…Furthermore, for certain drugs such as propofol, CL R,met has been investigated by analysing plasma drug and/or metabolite concentrations during the anhepatic stage of liver transplant (91). Importantly, the availability of the data from the anhepatic stage enabled IVIVE-PBPK-based predictions of propofol CL R,met and the relative contribution of kidney to overall propofol metabolism to be assessed (33). Finally, lower CL R of tacrolimus by cytochrome p450 (CYP) 3A5 expressers compared with non-expressers, along with experimental in vitro data generated using human kidney microsomes, suggests that renal metabolism of tacrolimus is relevant in CYP3A5 expressers (92).…”

Section: Renal Drug Disposition As a Results Of Multiple Processesmentioning

confidence: 99%

Section: In Vivo Activitymentioning

confidence: 99%

“…This includes limited use of PBPK models, allowing for simulation of plasma concentration-time profiles (33). There is a trend for underprediction of overall glucuronidation clearance using IVIVE, even when both hepatic and renal glucuronidation are accounted for (17,32,33). Use of the well-stirred model may bias IVIVE predictions for renal metabolism (17,32), although no suitable alternative, kidney-specific, model has yet been proposed.…”

Section: In Vivo Activitymentioning

confidence: 99%

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Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation

Scotcher

Jones²,

Posada

et al. 2016

AAPS J

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Abstract.It is envisaged that application of mechanistic models will improve prediction of changes in renal disposition due to drug-drug interactions, genetic polymorphism in enzymes and transporters and/or renal impairment. However, developing and validating mechanistic kidney models is challenging due to the number of processes that may occur (filtration, secretion, reabsorption and metabolism) in this complex organ. Prediction of human renal drug disposition from preclinical species may be hampered by species differences in the expression and activity of drug metabolising enzymes and transporters. A proposed solution is bottom-up prediction of pharmacokinetic parameters based on in vitro-in vivo extrapolation (IVIVE), mediated by recent advances in in vitro experimental techniques and application of relevant scaling factors. This review is a follow-up to the Part I of the report from the 2015 AAPS Annual Meeting and Exhibition (Orlando, FL; 25th-29th October 2015) which focuses on IVIVE and mechanistic prediction of renal drug disposition. It describes the various mechanistic kidney models that may be used to investigate renal drug disposition. Particular attention is given to efforts that have attempted to incorporate elements of IVIVE. In addition, the use of mechanistic models in prediction of renal drugdrug interactions and potential for application in determining suitable adjustment of dose in kidney disease are discussed. The need for suitable clinical pharmacokinetics data for the purposes of delineating mechanistic aspects of kidney models in various scenarios is highlighted.KEY WORDS: active renal excretion; human kidney transporters; human renal drug clearance; kidney disease; non-hepatic drug metabolism.

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“…and, being a lipophilic molecule, dis-tributed into fat tissues, from where it redistributes into the circulation 2. In the past, both bottom-up (PBPK)3 and top-down approaches (popPK)4 were applied to describe the PK of this compound. In this work, a combi-nation of the two (middle-out approach) was applied to describe propofol PK in children.…”

mentioning

confidence: 99%

O-9 Paediatric pbpk modelling of propofol using the middle out approach

Michelet

Bocxlaer

2017

Arch Dis Child

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IntroductionThe project SAFEPEDRUG aims to pro-vide guidelines for drug research in children, based on bottom-up and top-down approaches. Propofol, one of their model compounds, is extensively metabolised in liver and kidney.1 and, being a lipophilic molecule, dis-tributed into fat tissues, from where it redistributes into the circulation.2 In the past, both bottom-up (PBPK)3 and top-down approaches (popPK)4 were applied to describe the PK of this compound. In this work, a combi-nation of the two (middle-out approach) was applied to describe propofol PK in children.MethodsData from different trials were analysed using a 3-compartment-model in NONMEM. In vitro metabolism data was generated using the methodology from Gill et al.5 All data was then described using a full PBPK model in SimcypV16. In vivo clearances were either obtained starting from in vitro clearance or scaled back from the in vivo clearance values estimated using NONMEM. Once an accurate in vivo clearance was obtained, the adult mod-el was scaled to paediatrics and the resulting model was challenged with paediatric data.ResultsA CL of 1.07 L/h/kg and Vd of 822L were esti-mated using the population approach. In vitro CLint val-ues were consistent with literature, and an IVIVE would thus result in the same underprediction of total CL as described before. Therefore, the published model3 was examined to see which parameters could increase the predicted CLiv. It was found that estimating the B:P and fu resulted in a predicted average CLiv of 1.01 L/h/kg compared to 0.39 L/h/kg before. Using the retrograde approach based on literature data, a match between pre-dicted CLiv and NONMEM-derived CL was obtained. The model performed better than previous models and was able to describe PK for both long-and short-term infu-sions in adults. Extrapolation to children gave better re-sults compared to bottom-up or top-down models.ConclusionIn the past, PBPK and PopPK have mostly been used side by side to describe PK. However, a better result is achieved if both are combined. When studying a complex ADME compound such as propofol, a PBPK approach is often recommended. However, current in vitro systems and IVIVE are not yet optimised for these complexities. Therefore, the best strategy is to integrate in vivo data with in vitro studies. Once an adult PBPK model is built, it can be scaled to children using knowledge of the ontogeny and maturation, which implies a correctly predicted contribution of each subsystem to the systemic clearance.

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Application of a Physiologically Based Pharmacokinetic Model to Assess Propofol Hepatic and Renal Glucuronidation in Isolation: Utility of In Vitro and In Vivo Data

Cited by 26 publications

References 67 publications

Stereoselective Glucuronidation of Bupropion Metabolites In Vitro and In Vivo

Stereoselective Glucuronidation of Bupropion Metabolites In Vitro and In Vivo

Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation

O-9 Paediatric pbpk modelling of propofol using the middle out approach

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