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A Modified Compartmental Pharmacokinetic Model of Enterohepatic Circulation for Simvastatin in Healthy Mexican Subjects. A Pilot Study

Author(s): Melchor Alpízar-Salazar, Miguel Alejandro Trejo-Rangel, José de Jesús Reséndiz-Rojas, Tamara Daniela Frydman, Carlos Ramos-Mundo

Enterohepatic circulation (EHC) is a process that many drugs go through, in which, after extravascular administration, they are absorbed in the intestine, secreted in the bile and then reabsorbed during one or more circulation cycles that alter plasmatic concentrations of said drugs. The aim of this study was to compare a new pharmacokinetic model of EHC with the classic model of extravascular administration after administering Simvastatin. A single-center, randomized, controlled, prospective, longitudinal, single-dose, cross-over study was performed with a 7-day washout period, in healthy Mexican subjects. The plasma samples obtained were quantified with HPLC-MS / MS using a validated analytical method. Cmax, tmax, AUC0-24h and AUC0-∞ were determined, and both models were compared with the Akaike Information Criterion (AIC) and r^2. Results show that the pharmacokinetic parameters calculated with the EHC model are fairly similar to those obtained with the trapezoidal model, even more so than those obtained with the classic model. The AIC and r^2 criteria were lower for the EHC model (AIC=11.256 and 12.555, r^2=0.568 and 0.440) vs the classic model (AIC=9.382 and 9.195, r^2= 0.884 and 0.922). In conclusion, a new pharmacokinetic model for EHC was developed, and results confirmed that it adjusts well to experimental data, offering an alternative way to calculate Cmax, tmax and AUC0-t, and can also be adapted to other drugs that exhibit EHC as well.

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