Faster clearance of omeprazole in rats with acute renal failure induced by uranyl nitrate: contribution of increased expression of hepatic cytochrome P450 (CYP) 3A1 and intestinal CYP1A and 3A subfamilies

Abstract

It has been reported that omeprazole is mainly metabolized via hepatic cytochrome P450 (CYP) 1A1/2, CYP2D1 and CYP3A1/2 in male Sprague-Dawley rats, and the expression of hepatic CYP3A1 is increased in male Sprague-Dawley rats with acute renal failure induced by uranyl nitrate (U-ARF rats). Thus, the metabolism of omeprazole would be expected to increase in U-ARF rats. After intravenous administration of omeprazole (20 mgkg −1 ) to U-ARF rats, the area under the plasma concentration-time curve from time zero to infinity (AUC) was significantly reduced (371 vs 494 mgminmL), possibly due to the significantly faster non-renal clearance (56.6 vs 41.2 mL min −1 kg −1 ) compared with control rats. This could have been due to increased expression of hepatic CYP3A1 in U-ARF rats. After oral administration of omeprazole (40 mgkg −1 ) to U-ARF rats, the AUC was also significantly reduced (89.3 vs 235 mg minmL −1 ) compared with control rats. The AUC difference after oral administration (62.0% decrease) was greater than that after intravenous administration (24.9% decrease). This may have been primarily due to increased intestinal metabolism of omeprazole caused by increased expression of intestinal CYP1A and 3A subfamilies in U-ARF rats, in addition to increased hepatic metabolism.

Reduced clearance of ε-acetamidocaproic acid in rats with acute renal failure induced by uranyl nitrate

“…The plasma urea nitrogen concentrations in U‐ARF rats were higher than the reported ranges (5.0–29.0 mg/dl) in control rats [24] . Impaired kidney function in U‐ARF rats has been reported from another study [13–15] . However, despite impaired kidney function in U‐ARF rats, there was no discernible difference in the histology of kidneys between control and U‐ARF rats [13–15] …”

“…The sample was immediately centrifuged and 50 µl plasma was stored at −70°C (Revco ULT 1490 D‐N‐S; Western Mednics, Asheville, NC, USA) until analysis of EACA by LC‐MS/MS [13,19] . Procedures used for preparation and handling of the 24‐h urine sample and entire gastrointestinal tract (including its contents and faeces) sample at 24 h have been described previously [13–16,19] …”

“…Thus, we herein report the pharmacokinetic changes after intravenous and oral administration of zinc acexamate to rats with ARF‐induced by uranyl nitrate (U‐ARF). U‐ARF rats have been widely used as an animal model for ARF [13–15] . Furthermore, the mechanism of pharmacokinetic changes of EACA in the ARF state was investigated regarding hepatic/intestinal metabolism (in‐vitro microsome and tissue homogenate studies) and renal excretion (evaluation of urine flow dependency and interaction with probenecid).…”

Altered disposition of drugs in acute renal failure rat models: drug development strategies and perspectives

“…suggested thatt he rapid decline of lithium( CAS 17341-24-1) concentrationsfrom CSF in ARF rats wasdueto increased transporterexpression in the choroid plexus during ARF [16].The role of efflux mechanismwasalso confirmed forbothp rocainamide (CAS 614-39-1) and N-acetylprocainamide (CAS 32795-44-1) and the role of activated charcoaltof urtherenhancethe intestinal clearanceo fthe analytesw asr eported [47].The expression of organicc ation transporters hasbeen shownto bem odulated byARF in the kidneyand asac onsequenceareduced uptake of tetraethylammoniumcation wasobserved in the meduallaregion of rat'skidney [17].Theremaybeadistinctpossibility thaturemictoxinsgenerated during ARF mayr etardthe absorption process.Inthe casestudyof cyclosporine [51 -55], owing tosignificantgut accumulation of orallyadministered cyclosporine during ARF, one should bem indful of the effectcyclosporine mayhaveo no therco-administered agents sincecyclosporine isaknowni nhibitor of intestinale fflux related process [73].…”

“…Shim et al 2009 [17] Tetraethylammonium (56-34-8) Uranyl nitrate induced ARF Kidney tissue distribution relative to plasma was investigated in ARF vs control rats. Steady state distribution of tetraethylammonium was reduced by 15-fold in ARF rats as compared to control rats.…”