Relationship between Lipophilicity and Tubular Reabsorption for a Series of 5‐Alkyl‐5‐ethylbarbituric Acids in the Isolated Perfused Rat Kidney Preparation

Mayer, Joachim M.; Hall, Stephen D.; Rowland, Malcolm

doi:10.1002/jps.2600770416

Cited by 18 publications

(7 citation statements)

References 16 publications

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“…Details of predictions are listed Supplemental Material, Supplemental Table S14 and Morris, 2015; Burt et al, 2016;Scotcher et al, 2017). Models developed for the purpose of describing passive tubular reabsorption have allowed simulation of urine flow-dependent CL R of drugs with different permeability properties (Tang-Liu et al, 1983;Komiya, 1986;Mayer et al, 1988); however, these models did not account for the varying physiology of the renal tubule in a mechanistic and quantitative manner and therefore lack the ability to simulate intra-tubular drug concentrations. Whereas a mechanistic kidney model implemented within the whole-body PBPK model in the Simcyp simulator could, in principle, overcome such limitations, the utility of this model for prediction of tubular reabsorption and effects of physiologic changes in urine flow and pH has not been demonstrated so far (Neuhoff et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Towards Further Verification of Physiologically-Based Kidney Models: Predictability of the Effects of Urine-Flow and Urine-pH on Renal Clearance

Matsuzaki¹,

Scotcher²,

Darwich³

et al. 2018

J Pharmacol Exp Ther

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In vitro-in vivo extrapolation (IVIVE) of renal excretory clearance (CL R ) using the physiologically based kidney models can provide mechanistic insight into the interplay of multiple processes occurring in the renal tubule; however, the ability of these models to capture quantitatively the impact of perturbed conditions (e.g., urine flow, urine pH changes) on CL R has not been fully evaluated. In this work, we aimed to assess the predictability of the effect of urine flow and urine pH on CL R and tubular drug concentrations (selected examples). Passive diffusion clearance across the nephron tubule membrane was scaled from in vitro human epithelial cell line Caco-2 permeability data by nephron tubular surface area to predict the fraction reabsorbed and the CL R of caffeine, chloramphenicol, creatinine, dextroamphetamine, nicotine, sulfamethoxazole, and theophylline. CL R values predicted using mechanistic kidney model at a urinary pH of 6.2 and 7.4 resulted in prediction bias of 2.87-and 3.62-fold, respectively. Model simulations captured urine flow-dependent CL R , albeit with minor underprediction of the observed magnitude of change. The relationship between drug solubility, urine flow, and urine pH, illustrated in simulated intratubular concentrations of acyclovir and sulfamethoxazole, agreed with clinical data on tubular precipitation and crystal-induced acute kidney injury. This study represents the first systematic evaluation of the ability of the mechanistic kidney model to capture the impact of urine flow and urine pH on CL R and drug tubular concentrations with the aim of facilitating refinement of IVIVE-based mechanistic prediction of renal excretion.

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Section: Discussionmentioning

confidence: 99%

Towards Further Verification of Physiologically-Based Kidney Models: Predictability of the Effects of Urine-Flow and Urine-pH on Renal Clearance

Matsuzaki¹,

Scotcher²,

Darwich³

et al. 2018

J Pharmacol Exp Ther

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“…It is difficult to correlate clearance with physi-cochemical and molecular descriptors owing to the complexity of the biological system, the influence of transporters, and the vast range of sites and mechanisms of drug biotransformation and elimination [59]. Mayer et al [60] shows relation between renal clearance values and log D as follows:…”

Section: Volume Of Distribution Clearance and Drug Half-lifementioning

confidence: 99%

Insilico studies of organosulfur‐functional active compounds in garlic

Singh

2010

BioFactors

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Garlic has been used medicinally since antiquity because of its antimicrobial activity, anticancer activity, antioxidant activity, ability to reduce cardiovascular diseases, improving immune functions, and antidiabetic activities and also in reducing cardiovascular diseases and improving immune functions. Recent studies identify that the wide variety of medicinal functions are attributed to the sulfur compounds present in garlic. Epidemiological observations and laboratory studies in animal models have also showed anticarcinogenic potential of organosulfur compounds of garlic. In this study, in silico analysis of organosulfur compounds is reported using the methods of theoretical chemistry to elucidate the molecular properties of garlic as it is more time and cost efficient, reduces the number of wet experiments, and offers the possibility of replacing some animal tests with suitable in silico models. The analysis of molecular descriptors defined by Lipinski has been done. The solubility of drug in water has been determined as it is of useful importance in the process of drug discovery from molecular design to pharmaceutical formulation and biopharmacy. All toxicities associated with candidate drug have been calculated. P-Glycoprotein expressed in normal tissues as a cause of drug pharmacokinetics and pharmacodynamics has been examined. Drug-plasma protein binding and volume of distribution have also been calculated. To avoid rejection of drugs, it is becoming more important to determine pK(a), absorption, polar surface area, and other physiochemical properties associated with a drug, before synthetic work is undertaken. The present in silico study is aimed at examining these compounds of garlic to evaluate its possible efficacy and toxicity under conditions of actual use in humans.

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“…Models of drug reabsorption in particular should account for the different tubular filtrate flow rates found along different regions of the nephron. This can be achieved by either mathematically describing the simultaneous reabsorption of water and drug along the length of the tubule, or using a model with multiple compartments that each represents a region of the tubule with respective tubular flow rate value (14,23,(47)(48)(49)(50). The latter approach was applied in models of transporter mediated renal reabsorption of γ-hydroxybutyric acid in rat (36,44).…”

Section: Prediction Of Renal Excretion Of Drugs Within Pbpk Paradigmmentioning

confidence: 99%

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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Relationship between Lipophilicity and Tubular Reabsorption for a Series of 5‐Alkyl‐5‐ethylbarbituric Acids in the Isolated Perfused Rat Kidney Preparation

Cited by 18 publications

References 16 publications

Towards Further Verification of Physiologically-Based Kidney Models: Predictability of the Effects of Urine-Flow and Urine-pH on Renal Clearance

Towards Further Verification of Physiologically-Based Kidney Models: Predictability of the Effects of Urine-Flow and Urine-pH on Renal Clearance

Insilico studies of organosulfur‐functional active compounds in garlic

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

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