Physiologically-Based Pharmacokinetic Modeling for Drug-Drug Interactions of Procainamide and N-Acetylprocainamide with Cimetidine, an Inhibitor of rOCT2 and rMATE1, in Rats

Abstract

Previous observations demonstrated that cimetidine decreased the clearance of procainamide (PA) and/or N-acetylprocainamide (NAPA; the primary metabolite of PA) resulting in the increased systemic exposure and the decrease of urinary excretion. Despite an abundance of in vitro and in vivo data regarding pharmacokinetic interactions between PA/NAPA and cimetidine, however, a mechanistic approach to elucidate these interactions has not been reported yet. The primary objective of this study was to construct a physiological model that describes pharmacokinetic interactions between PA/NAPA and cimetidine, an inhibitor of rat organic cation transporter 2 (rOCT2) and rat multidrug and toxin extrusion proteins (rMATE1), by performing extensive in vivo and in vitro pharmacokinetic studies for PA and NAPA performed in the absence or presence of cimetidine in rats. When a single intravenous injection of PA HCl (10 mg/kg) was administered to rats, co-administration of cimetidine (100 mg/kg) significantly increased systemic exposure and decreased the systemic (CL) and renal (CLR) clearance of PA, and reduced its tissue distribution. Similarly, cimetidine significantly decreased the CLR of NAPA formed by the metabolism of PA and increased the AUC of NAPA. Considering that these drugs could share similar renal secretory pathways (e.g., via rOCT2 and rMATE1), a physiologically-based pharmacokinetic (PBPK) model incorporating semi-mechanistic kidney compartments was devised to predict drug-drug interactions (DDIs). Using our proposed PBPK model, DDIs between PA/NAPA and cimetidine were successfully predicted for the plasma concentrations and urinary excretion profiles of PA and NAPA observed in rats. Moreover, sensitivity analyses of the pharmacokinetics of PA and NAPA showed the inhibitory effects of cimetidine via rMATE1 were probably important for the renal elimination of PA and NAPA in rats. The proposed PBPK model may be useful for understanding the mechanisms of interactions between PA/NAPA and cimetidine in vivo.

Effects of 1α,25-Dihydroxyvitamin D3 on the Pharmacokinetics of Procainamide and Its Metabolite N-Acetylprocainamide, Organic Cation Transporter Substrates, in Rats with PBPK Modeling Approach

“…The non-specific binding of PA was 7.52%, suggesting that non-specific binding of the drug to the ultrafiltration membrane or apparatus may be negligible. The free fraction of PA HCl in the plasma of control rats (87.1 ± 0.85%) did not differ from that in the plasma of 1,25(OH)2D3-treated rats (87.4 ± 3.42%), which is consistent with the results of the previous study [22]. The recovery was 99.4 ± 4.36% and 108 ± 4.11% for the plasma from the control and 1,25(OH)2D3-treated rats, respectively.…”

“…Following the intravenous administration of PA HCl at 10 mg/kg to the control and 1,25(OH) 2 D 3 -treated rats, the plasma concentration-time profiles of PA and its metabolite NAPA were determined, as shown in Figure 3. The relevant pharmacokinetic parameters determined in the control group (Table 1) were not significantly different from those obtained in a previous study [22]. This suggests that treating rats with the vehicle (i.e., 0.0452% ethanol in filtered corn oil; 1 mL/kg) had no significant effect on the systemic pharmacokinetics of PA and NAPA.…”

Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson’s Disease

“…The linearity, precision, and accuracy for PCIII were observed within the acceptable ranges. The tissue concentration level was expressed as a unit of PCIII amount (ng)/g tissue, as described previously [21].…”

Development and Evaluation of Poorly Water-Soluble Celecoxib as Solid Dispersions Containing Nonionic Surfactants Using Fluidized-Bed Granulation

“…To investigate the possibility of enhanced absorption for the optimized SDG (CXB/Cre-RH = 1:0.5) in vivo, oral pharmacokinetic studies of celecoxib powders, a celecoxib marketed product, and the SDGs were performed at a dose of 5 mg/kg in fasted male Sprague Dawley (SD) rats. All animal experiments were performed in accordance with the Guidelines for Animal Care and Use issued by Gachon University, as described previously [36]. Experimental protocols regarding the animals used in this study were reviewed and approved by the Animal Care and Use Committee of the Gachon University (#GIACUC-R2018004, approval date on 11 May 2018).…”