Abstract
In the evolving paradigm of drug development it is a reasonable strategy to avoid
and/or anticipate potential risks in drug development for select drugs by performing
in vitro and/or preclinical studies in appropriate animal models. The availability of acute
renal failure (ARF) rat models provides an opportunity to explore the pharmacokinetic
disposition of drugs and associated metabolites in conditions that mimic the pathophysiology
of the disease in humans. Such studies may help in drug(s) selection for development,
differentiating certain drug classes, and/or arriving at a dose strategy decision
in the clinic.
Scores of compounds, belonging to various therapeutic areas, have undergone pharmacokinetic
investigations in ARF models induced by uranyl nitrate (CAS 10102-06-4), glycerol
(CAS 56-81-5), cisplatin (CAS 15663-27-1) or gentamicin (CAS 1403-66-3) in rats. The
published pharmacokinetic disposition data has unequivocally suggested that ARF conditions
leads to decreased renal elimination of the drug and associated metabolites; however,
the influence on the overall body clearance is dependent on the propensity of the
contribution of renal versus non-renal mechanisms of elimination. In the case studies
assembled for this review, 52.5% of the drugs showed an increased drug exposure, 35%
of the drugs showed a decreased drug exposure and 12.5% of the drugs showed no altered
exposure, in ARF rat models relative to control rats. Interestingly, ARF can have
an overall impact on drug absorption, distribution, metabolism, local transport and
biliary excretion. Hence, the overall pharmacokinetic disposition may have to be interpreted
with caution during ARF since there is the potential for competiting pathways to co-exist.
For instance, due to reduced renal elimination as a result of kidney insult caused
by ARF, compensatory biliary excretion mechanism may occur. Alternatively, intestinal
and/or hepatic enzymatic expression level may go up to facilitate enhanced metabolism.
However, there may be instances where uraemic toxins floating in the circulation may
block the metabolism and/or may also retard the absorption process.
This review covers: 1) an illustration of a number of case studies providing tabulated
information on the key altered pharmacokinetic parameters observed in ARF and the
hypothesized mechanistic explanation; 2) a comprehensive description of altered absorption,
distribution, metabolism, excretion and efflux transport related changes observed
during ARF; 3) a general framework for drug development strategies and 4) a succinct
discussion on the overall perspectives of the applicability of ARF rat models.
Key words
Acute renal failure - Case studies - Pharmacokinetic parameters - Rat models
