Pharmacokinetic changes of cefdinir and cefditoren and its molecular mechanisms in acute kidney injury in rats.

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Wang H, Sun P, Wang C, Meng Q, Liu Z, Huo X, Sun H, Ma X, Peng J, Liu K

Pharmacokinetic changes of cefdinir and cefditoren and its molecular mechanisms in acute kidney injury in rats.

J Pharm Pharmacol. 2018 Nov;70(11):1503-1512. doi: 10.1111/jphp.12994. Epub 2018 Jul 25.

PubMed ID

30047127 [ View in PubMed

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Abstract

OBJECTIVES: Acute kidney injury (AKI) was a common organ damage that often occurred after cisplatin. This study was aimed at investigating the pharmacokinetic changes of cefdinir and cefditoren in AKI rats, and elucidating the possible molecular mechanisms. METHODS: The renal injury model was established by intraperitoneal injection of cisplatin (12 mg/kg). Plasma creatinine, blood urea nitrogen, the mRNA expression of Kim-1, hematoxylin and eosin staining and Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) assay were used to measure the degree of renal damage. On this basis, the pharmacokinetic changes of cefdinir and cefditoren were investigated in normal and AKI rats. RT-PCR and Western blot were performed to clarify the molecular mechanisms for the changes in the related transporters expression. KEY FINDINGS: The cumulative urinary excretion of cefdinir was significantly decreased and the plasma concentration was remarkably increased in AKI rats. The expression of organic anion transporter 1 (Oat1) and Oat3 in kidney was decreased. However, pharmacokinetics of cefditoren was not influenced. The expression of organic anion-transporting polypeptide 1a1 (Oatp1a1), Oatp1a4, Oatp1b2 and multidrug resistance-associated protein 2 (Mrp2) in liver was unchanged in AKI rats. CONCLUSIONS: The molecular mechanism of decreased expression of Oat1 and Oat3 was achieved through activating p53, and then increasing the expression of Bax and Caspase-3 and down regulating Bcl-2 in AKI rats. On this basis, the cumulative urinary excretion of cefdinir was significantly decreased and the plasma concentration of cefdinir was remarkably increased in AKI rats. However, the pharmacokinetic changes of cefditoren were not observed. Accordingly, cephalosporin antibiotics such as cefditoren should be firstly selected for the treatment in patients with AKI in clinic.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Cefdinir	Solute carrier family 22 member 8	Protein	Humans	Unknown	Substrate	Details