Predicting points of departure for risk assessment based on in vitro cytotoxicity data and physiologically based kinetic (PBK) modeling: The case of kidney toxicity induced by aristolochic acid I

Abdullah, Raja Syamsul Azmir Raja; Alhusainy, Wasma; Woutersen, Jasper; Rietjens, Ivonne M.C.M.; Punt, Ans

doi:10.1016/j.fct.2016.03.017

Cited by 43 publications

(44 citation statements)

References 60 publications

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“…S9 protein yields of mouse liver, kidneys, and small intestine were 121, 90.0, and 49.0 mg S9 protein/g tissue, respectively. These parameters were consistent with the values in previous reports (Davies and Morris, 1993;Abdullah et al, 2016). We also calculated the DPP-4 activity in whole plasma (nmol/min/plasma) using a reported plasma volume in mouse, which is 1.0 mL (Davies and Morris, 1993).…”

Section: Resultssupporting

confidence: 89%

Hepatic Dipeptidyl Peptidase-4 Controls Pharmacokinetics of Vildagliptin In Vivo

et al. 2016

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The main route of elimination of vildagliptin, which is an inhibitor of dipeptidyl peptidase-4 (DPP-4), in humans is cyano group hydrolysis to produce a carboxylic acid metabolite M20.7. Our in vitro study previously demonstrated that DPP-4 itself greatly contributed to the hydrolysis of vildagliptin in mouse, rat, and human livers. To investigate whether hepatic DPP-4 contributes to the hydrolysis of vildagliptin in vivo, in the present study, we conducted in vivo pharmacokinetics studies of vildagliptin in mice coadministered with vildagliptin and sitagliptin, which is another DPP-4 inhibitor, and also in streptozotocin (STZ)-induced diabetic mice. The area under the plasma concentration-time curve (AUC) value of M20.7 in mice coadministered with vildagliptin and sitagliptin was significantly lower than that in mice administered vildagliptin alone (P < 0.01). Although plasma DPP-4 expression level was increased 1.9-fold, hepatic DPP-4 activity was decreased in STZ-induced diabetic mice. The AUC values of M20.7 in STZ-induced diabetic mice were lower than those in control mice (P < 0.01). Additionally, the AUC values of M20.7 significantly positively correlated with hepatic DPP-4 activities in the individual mice (Rs = 0.943, P < 0.05). These findings indicated that DPP-4 greatly contributed to the hydrolysis of vildagliptin in vivo and that not plasma, but hepatic DPP-4 controlled pharmacokinetics of vildagliptin. Furthermore, enzyme assays of 23 individual human liver samples showed that there was a 3.6-fold interindividual variability in vildagliptin-hydrolyzing activities. Predetermination of the interindividual variability of hepatic vildagliptin-hydrolyzing activity might be useful for the prediction of blood vildagliptin concentrations in vivo.

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Section: Resultssupporting

confidence: 89%

Hepatic Dipeptidyl Peptidase-4 Controls Pharmacokinetics of Vildagliptin In Vivo

et al. 2016

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“…As nephrotoxicity models become more physiologically relevant, their clinical predictive value will lie in screening not only for single drug effects but also for drug–drug interactions and the effects of individual variations such as the effects of underlying kidney disease or CYP enzyme polymorphisms on drug metabolism and toxicity 100,149,150 . Such analyses will require in vitro-to-in vivo extrapolations, involving mathematical models that can numerically simulate the behaviour of a drug in a complex system using results obtained experimentally in an in vitro system as the input parameter.…”

Section: Future Directionsmentioning

confidence: 99%

Advances in predictive in vitro models of drug-induced nephrotoxicity

et al. 2018

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In vitro screens for nephrotoxicity are currently poorly predictive of toxicity in humans. Although the functional proteins that are expressed by nephron tubules and mediate drug susceptibility are well known, current in vitro cellular models poorly replicate both the morphology and the function of kidney tubules and therefore fail to demonstrate injury responses to drugs that would be nephrotoxic in vivo. Advances in protocols to enable the directed differentiation of pluripotent stem cells into multiple renal cell types and the development of microfluidic and 3D culture systems have opened a range of potential new platforms for evaluating drug nephrotoxicity. Many of the new in vitro culture systems have been characterized by the expression and function of transporters, enzymes, and other functional proteins that are expressed by the kidney and have been implicated in drug-induced renal injury. In vitro platforms that express these proteins and exhibit molecular biomarkers that have been used as readouts of injury demonstrate improved functional maturity compared with static 2D cultures and represent an opportunity to model injury to renal cell types that have hitherto received little attention. As nephrotoxicity screening platforms become more physiologically relevant, they will facilitate the development of safer drugs and improved clinical management of nephrotoxicants.

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“…In 1999, the British Committee on Safety of Medicines (CSM) suggested that the use of botanical drugs containing AA be banned immediately . In October 2000, the European Agency for the Evaluation of Medicinal Products issued a position paper that warned European Union Member States “to take steps to ensure that the public is protected from exposure to aristolochic acids arising from the deliberate use of Aristolochia species or as a result of confusion with other botanical ingredients.” On 2 November 2000, the World Health Organization (WHO) issued a similar warning in drug communications. Various countries, including Malaysia, Spain, Japan, Egypt, Austria and the Philippines, have followed suit .…”

Section: Commentarymentioning

confidence: 99%

“…7 In October 2000, the European Agency for the Evaluation of Medicinal Products issued a position paper that warned European Union Member States "to take steps to ensure that the public is protected from exposure to aristolochic acids arising from the deliberate use of Aristolochia species or as a result of confusion with other botanical ingredients." 8 Austria and the Philippines, have followed suit. 9 In 2001, the US FDA advised consumers to stop using products containing AA, and the sale of AA-containing botanical products has also been prohibited in several other countries, including Canada, New Zealand, Australia and many Asian countries.…”

Section: Attitudes In and Measures Taken By Different Countries Regmentioning

confidence: 99%

Recognition of the toxicity of aristolochic acid

Zhang

Xin²,

Sun

et al. 2018

J Clin Pharm Ther

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Summary What is Known and Objective Aristolochic acid (AA) is an abundant compound in Aristolochia plants and various natural herbs. In the 1990s, a slimming formula used in Belgium that contains Aristolochia fangchi was reported to cause kidney damage and bladder cancer, and aristolochic acid nephropathy (AAN) is now well recognized worldwide. In October 2017, researchers reported an AA signature that is closely associated with hepatocellular carcinoma (HCC) worldwide. Comment There are differing opinions on the toxicity of AA, and different countries have taken different measures to address the issue. There is a lack of clarity on the causal role of AA in hepatocarcinogenesis and on the potential underlying mechanisms for the reported nephrotoxicity and carcinogenicity. The toxicity of AA differs depending on gender and age, and other risk factors that could explain the variability in the toxicity of AA remain to be identified. What is New and Conclusion Whether preparations containing AA, such as many Chinese medicines, should be used remains controversial, and this issue warrants further investigation before definite conclusions can be drawn.

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Predicting points of departure for risk assessment based on in vitro cytotoxicity data and physiologically based kinetic (PBK) modeling: The case of kidney toxicity induced by aristolochic acid I

Cited by 43 publications

References 60 publications

Hepatic Dipeptidyl Peptidase-4 Controls Pharmacokinetics of Vildagliptin In Vivo

Hepatic Dipeptidyl Peptidase-4 Controls Pharmacokinetics of Vildagliptin In Vivo

Advances in predictive in vitro models of drug-induced nephrotoxicity

Recognition of the toxicity of aristolochic acid

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