Effects of the inhibition of intestinal P‐glycoprotein on aliskiren pharmacokinetics in cynomolgus monkeys

Abstract

Aliskiren is a substrate for P-glycoprotein (P-gp) and is metabolized via cytochrome P450 3A4 (CYP3A4). The aim of the present study was to assess whether P-gp influenced the pharmacokinetics of aliskiren and also if drug-drug interactions (DDIs) mediated through P-gp could be reproduced in cynomolgus monkeys. The study investigated the pharmacokinetics of aliskiren in mdr1a/1b gene-deficient (P-gp KO) and wild-type (WT) mice. The area under the plasma concentration-time curve (AUC) following the oral administration of aliskiren was 6.9-fold higher in P-gp KO mice than in WT mice, while no significant differences were observed in the AUC or total plasma clearance following the intravenous administration of aliskiren to P-gp KO mice. Then the pharmacokinetics of aliskiren were evaluated and DDIs between aliskiren and P-gp inhibitors, such as cyclosporin A (CsA) and zosuquidar, examined in cynomolgus monkeys. The AUC for aliskiren were 8.3- and 42.1-fold higher after the oral administration of aliskiren with the concomitant oral administration of zosuquidar and CsA at doses of 10 and 30 mg/kg, respectively. In contrast, the AUC after the intravenous and oral administration of aliskiren was not significantly affected by the oral administration of zosuquidar or intravenous administration of CsA, respectively. These results indicated that P-gp strictly limited the intestinal absorption of aliskiren in mice and monkeys, and also that the effects of intestinal P-gp inhibition by CsA or zosuquidar on the pharmacokinetics of aliskiren were sensitively reproduced in monkeys. In conclusion, aliskiren can be used as a sensitive substrate to evaluate intestinal P-gp inhibition in monkeys.

Pre‐incubation with cyclosporine A potentiates its inhibitory effects on pitavastatin uptake mediated by recombinantly expressed cynomolgus monkey hepatic organic anion transporting polypeptide

“…In cynomolgus monkeys, the I max was 921 ng/ml, the k a was 0.67 h −1 , and the lag time was 0.92 h (calculated using WinNonlin version 6.3, PK Model 4). The f b in cynomolgus monkeys was 0.013, calculated from the unbound fraction of cyclosporine A in plasma (0.029) divided by the blood/plasma concentration ratio ( R B : 2.3, in‐house data). The F A · F G in cynomolgus monkeys was calculated by the following equations: where E H , CL total , F and F H are the hepatic extraction ratio, total plasma clearance, bioavailability and hepatic availability, respectively.…”

“…The F A · F G in cynomolgus monkeys was calculated by the following equations: where E H , CL total , F and F H are the hepatic extraction ratio, total plasma clearance, bioavailability and hepatic availability, respectively. To calculate the above equation, literature was used that reported the pharmacokinetic parameters of cyclosporine A after intravenous and oral administration at 1 and 100 mg/kg, respectively . CL total was calculated as the intravenous dose divided by the AUC after intravenous administration.…”

“…The maximum unbound concentration of rifampicin at the inlet to the liver in monkeys was not calculated because some pharmacokinetic parameters were unknown. [12]; unbound fraction in the plasma: 0.029 [20]; R B : 2.3, In-house data; F A · F G : 0.338, calculation using previously reported pharmacokinetic parameters [20], See detail in Methods. ; k a : 0.67 h À1 , Calculation using previously reported pharmacokinetic profile [12], See detail in Methods.…”

“…In cynomolgus monkeys, the I max was 921 ng/ml, the k a was 0.67 h À1 , and the lag time was 0.92 h (calculated using WinNonlin version 6.3, PK Model 4). The f b in cynomolgus monkeys was 0.013, calculated from the unbound fraction of cyclosporine A in plasma (0.029) [20] divided by the blood/plasma concentration ratio (R B : 2.3, in-house data). The F A ·F G in cynomolgus monkeys was calculated by the following equations:…”

Predicting the Changes in Oral Absorption of Weak Base Drugs Under Elevated Gastric pH Using an In Vitro–In Silico–In Vivo Approach: Case Examples—Dipyridamole, Prasugrel, and Nelfinavir

“…The oral absorption of some drugs occurs via influx and efflux transporters that exist in the intestinal epithelial cells and their carrier-mediated transport can be affected by coadministered pharmaceutical ingredients (drugs or excipients) resulting in a change in the drug's plasma profile. [2][3][4] Another possible DDI that is related to oral drug absorption is via the decrease in gastric acidity due to coadministration of an acid reducer, for example, proton pump inhibitors (PPIs), histamine H 2 receptor antagonists (H 2 antagonists) and antacids. Under elevated gastric pH conditions, the oral absorption of some weak base drugs may be decreased due to lower solubility.…”