Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

Abstract

Imaging technologies can evaluate many different biological processes in vitro (in cell culture models) and in vivo (in animals and humans), and many are used routinely in investigation of human liver diseases. Some of these methods can help understand liver toxicity caused by drugs in vivo in animals, and druginduced liver injury (DILI) which arises in susceptible humans. Imaging could aid assessment of the relevance to humans in vivo of toxicity caused by drugs in animals (animal/human translation), plus toxicities observed using in vitro model systems (in vitro/in vivo translation). Technologies and probe substrates for quantitative evaluation of hepatobiliary transporter activities are of particular importance. This is due to the key role played by sinusoidal transporter mediated hepatic uptake in DILI caused by many drugs, plus the strong evidence that inhibition of the hepatic bile salt export pump (BSEP) can initiate DILI. Imaging methods for investigation of these processes are reviewed in this chapter, together with their scientific rationale, and methods of quantitative data analysis. In addition to providing biomarkers for investigation of DILI, such approaches could aid the evaluation of clinically relevant drug-drug interactions mediated via hepatobiliary transporter perturbation.

Validation of Pharmacological Protocols for Targeted Inhibition of Canalicular MRP2 Activity in Hepatocytes Using [99mTc]mebrofenin Imaging in Rats

“…However, imaging protocols for selective determination of MRP2 activity at the canalicular interface are currently not available. The availability of such an imaging protocol would be of high interest to predict MRP2-mediated DILI in drug development [ 41 ] and to study the effect of genetic polymorphisms or liver disease on hepatic MRP2 activity [ 42 ].…”

“…Thus, low-dose CsA may be useful both for a selective determination of MRP2 activity and for an improved measurement of OATP activity. Low-dose CsA therefore enriches the toolbox of available inhibitors for pharmacokinetic studies [ 41 ].…”

A Novel Physiologically Based Model of Creatinine Renal Disposition to Integrate Current Knowledge of Systems Parameters and Clinical Observations

“…efflux rates, although limited examples have been reported to date for liver. 13,44 The simultaneous estimation of P app and CL int presented additional model optimization challenges, including multiobjective optimization and model noise leading to nonsmooth objective functions. These were explored in a pragmatic manner (details in Supplemental Material, Section 6).…”

Challenges of non-clinical safety testing for biologics: A Report of the 9th BioSafe European Annual General Membership Meeting

“…The focus for this consortium is in imaging-based approaches for detection and characterization of druginduced liver injury (DILI) and drug-induced interstitial lung disease (DIILD), as well as metabolic therapies that are included in our approach to better address bio-distribution of biologics, recognizing that drug safety is crucial in all disease areas. 41 TRISTAN LIVER IMAGING PROJECT: Inhibition of hepatobiliary transporters (particularly bile salt export pump) has been identified as a key initiating mechanism by which drugs may cause DILI. Furthermore, inhibition of hepatic uptake transporters may cause elevated drug concentrations in plasma, while inhibition of biliary efflux transporters can cause intra-hepatocyte drug accumulation; both of these processes could result in DDIs.…”

“…The focus for this consortium is in imaging-based approaches for detection and characterization of drug-induced liver injury (DILI) and drug-induced interstitial lung disease (DIILD), as well as metabolic therapies that are included in our approach to better address bio-distribution of biologics, recognizing that drug safety is crucial in all disease areas. 41 …”