Influence of cancer cachexia on drug liver metabolism and renal elimination in rats

Abstract

BackgroundBody wasting and cachexia change body composition and organ function, with effects on drug pharmacokinetics. The aim of this study was to investigate how cancer and cancer cachexia modify liver metabolism and renal drug elimination in rats.MethodsNine male Wistar-Han rats received a single oral dose of midazolam and propranolol (markers of hepatic metabolism), and 10 rats received single intravenous dose of iohexol, a marker of glomerular filtration rate. After drug delivery, multiple dried blood samples were obtained within 2 h post-dose to evaluate drug pharmacokinetic profiles. After baseline sampling (D0), rats were injected with tumour cells. Drug application and blood sampling were repeated when rats developed tumours (Day 5—D5), and when rats were severely cachectic (Day 10—D10). Clearance (CL) and volume of distribution (Vd) of drugs were assessed with non-linear mixed effects modelling. Weight and body composition were measured on D0 and D10 and were related to pharmacokinetic parameters.ResultsAll three drugs showed non-significant trend towards increased CL and Vd on D5. On D10, midazolam and propranolol CL and midazolam Vd significantly decreased from baseline (−80.5%, −79.8%, and −72.0%, respectively, P < 0.05 for all). Iohexol CL decreased by 29.8% from baseline value on D10, which was related to body weight loss (Pearson's r = 0.837, P = 0.019).ConclusionsHepatic metabolism and renal drug elimination are significantly reduced in cachexia, which could increase risk of dose-related adverse events.

Cardiac cachexia: hic et nunc

“…The scientific community is much engaged in interventional trials to find a remedy for muscle wasting and cachexia. It should be emphasized that translation of benefits from the non‐cachectic population to cachexia may not be straightforward as drug pharmacokinetics changes with body wasting . Ongoing trials are heterogenous in design and include a wide span of chronic disease .…”

“…It should be emphasized that translation of benefits from the non-cachectic population to cachexia may not be straightforward as drug pharmacokinetics changes with body wasting. 168,169 Ongoing trials are heterogenous in design and include a wide span of chronic disease. 94,112 A direct comparison of findings will be difficult as enrolment criteria (including sarcopenia/cachexia definition) vary and because different endpoints are being pursued.…”

Oodles of opportunities: the Journal of Cachexia, Sarcopenia and Muscle in 2017

“…Original Article 13 38 10 Dupuy Searching for a relevant definition of sarcopenia: results from the cross-sectional EPIDOS study Original Article 13 39…”

ACT‐ONE ‐ ACTION at last on cancer cachexia by adapting a novel action beta‐blocker

“…One of the aspects that deserve attention is drug dosing and pharmacokinetics. Body wasting and cachexia modulate not only chemotherapy regimens but have the potential to influence drug metabolism in general . Whether the longer survival under beta‐blocker therapy is related to improved nutritional status remains to be assessed.…”