Xenobiotic Metabolism: The Effect of Acute Kidney Injury on Non-Renal Drug Clearance and Hepatic Drug Metabolism

Abstract

Acute kidney injury (AKI) is a common complication of critical illness, and evidence is emerging that suggests AKI disrupts the function of other organs. It is a recognized phenomenon that patients with chronic kidney disease (CKD) have reduced hepatic metabolism of drugs, via the cytochrome P450 (CYP) enzyme group, and drug dosing guidelines in AKI are often extrapolated from data obtained from patients with CKD. This approach, however, is flawed because several confounding factors exist in AKI. The data from animal studies investigating the effects of AKI on CYP activity are conflicting, although the results of the majority do suggest that AKI impairs hepatic CYP activity. More recently, human study data have also demonstrated decreased CYP activity associated with AKI, in particular the CYP3A subtypes. Furthermore, preliminary data suggest that patients expressing the functional allele variant CYP3A5*1 may be protected from the deleterious effects of AKI when compared with patients homozygous for the variant CYP3A5*3, which codes for a non-functional protein. In conclusion, there is a need to individualize drug prescribing, particularly for the more sick and vulnerable patients, but this needs to be explored in greater depth.

UPLC-Q-TOF/MS-based screening and identification of two major bioactive components and their metabolites in normal and CKD rat plasma, urine and feces after oral administration of Rehmannia glutinosa Libosch extract

“…Drug disposition process in healthy humans in vivo has been shown different from patients with CKD [21][22][23]. Patients with CKD have reduced hepatic metabolism of drugs, via the cytochrome P450 (CYP) enzyme group [24].…”

The 6R’s of drug induced nephrotoxicity

“…However, research on drug dosing in AKI is limited. More information is needed on kidney function estimation in AKI, the impact of tubular function and metabolism of drugs during AKI and pharmacokinetic changes in AKI [71–73]. Enhancing this research will translate to the mitigation of additional risk and in turn enhanced recovery from a nephrotoxic event.…”

Comparative pharmacokinetics of catalpol and acteoside in normal and chronic kidney disease rats after oral administration of Rehmannia glutinosa extract

“…Patients with CKD are at increased risk of developing acute kidney injury and subsequently requiring renal replacement therapy (Panwar et al, 2013). Thus, when RG is used by patients with CKD, the drug pharmacokinetic behavior in vivo could be affected by the altered drug disposition (Dixon et al, 2014;Sun et al, 2006;Verbeeck and Musuamba 2009). Thus, when RG is used by patients with CKD, the drug pharmacokinetic behavior in vivo could be affected by the altered drug disposition (Dixon et al, 2014;Sun et al, 2006;Verbeeck and Musuamba 2009).…”