Increased Susceptibility to Methotrexate-Induced Toxicity in Nonalcoholic Steatohepatitis

Abstract

Hepatic drug metabolizing enzymes and transporters play a crucial role in determining the fate of drugs, and alterations in liver function can place individuals at greater risk for adverse drug reactions (ADRs). We have shown that nonalcoholic steatohepatitis (NASH) leads to changes in the expression and localization of enzymes and transporters responsible for the disposition of numerous drugs. The purpose of this study was to determine the effect of NASH on methotrexate (MTX) disposition and the resulting toxicity profile. Sprague Dawley rats were fed either a control or methionine-choline-deficient diet for 8 weeks to induce NASH, then administered a single ip vehicle, 10, 40, or 100 mg/kg MTX injection followed by blood, urine, and feces collection over 96 h with terminal tissue collection. At the onset of dosing, Abcc1-4, Abcb1, and Abcg2 were elevated in NASH livers, whereas Abcc2 and Abcb1 were not properly localized to the membrane, similar to that previously observed in human NASH. NASH rodents receiving 40-100 mg/kg MTX exhibited hepatocellular damage followed by initiation of repair, whereas damage was absent in controls. NASH rodents receiving 100 mg/kg MTX exhibited slightly greater renal toxicity, indicating multiple organ toxicity, despite the majority of the dose being excreted by 6 h. Intestinal toxicity in NASH however, was strikingly less severe than controls, and coincided with reduced fecal MTX excretion. Because MTX-induced gastrointestinal toxicity limits the dose escalation necessary for cancer remission, these data suggest a greater risk for life-threatening MTX-induced hepatic and renal toxicity in NASH in the absence of overt gastrointestinal toxicity.

Mechanistic Basis of Altered Morphine Disposition in Nonalcoholic Steatohepatitis

“…In addition, MRP2/Mrp2 has garnered much interest due to the observation that in NASH, this transporter appears to be mislocalized , a phenomenon that also occurs in cholestasis and acute oxidative stress (Mottino et al, 2002;Sekine et al, 2006), and was confirmed in this study via immunohistochemistry. Several previous disposition studies have demonstrated a shift from biliary excretion of known MRP2/Mrp2 substrates and metabolites (Lickteig et al, 2007;Hardwick et al, 2012Hardwick et al, , 2014 to an increased systemic exposure, providing credence to the notion that MRP2/Mrp2 has diminished function in NASH. Accordingly, this study reports the altered disposition of another glucuronide, a common shared substrate for the MRP2/MRP3 system.…”

Preventing and Managing Toxicities of High-Dose Methotrexate

“…Although these have not been documented to complicate HDMTX, avoiding alcohol and controlling hepatitis infection before HDMTX is warranted to minimize risk. Conversely, existing steatohepatitis may increase methotrexate toxicity [25]. …”

Nonalcoholic steatohepatitis in precision medicine: Unraveling the factors that contribute to individual variability

“…Therefore, it is imperative that accurate diagnoses of disease be made so that correct liver phenotype can be either assessed empirically or attributed to the patient so that the correct drug dose is prescribed. In recent years, NASH is one liver disease for which there has been a considerable accrual of evidence to support its inclusion as an environmental factor in precision medicine (Clarke, et al, 2014a, 2014b; Fisher et al, 2009, 2008; Hardwick et al, 2011, 2012, 2014; N. Li et al, 2004; Lickteig et al, 2007).…”