PREDICTION OF DRUG-DRUG INTERACTION POTENTIAL OF SULFONYL UREAS ON THE DISPOSITION OF ANTI-HYPERLIPIDEMIA DRUGS-MATHEMATICAL MODELING APPROACH.
As similar to metabolic pathways or metabolism of drug is inhibited competitively or by other pathways, the inhibition can be happening at the drug transport level which is also critical alongside other disposition pathways. Advances in the understanding of drug metabolic pathways and drug transport process help in the estimation of degree of invivo interaction in vitro through certain parameters like the [I]/Ki ratio. Such equations employ a blend of in vivo and in vitro derived parameters to estimate the fold change in the AUC ratio in the presence and absence of inhibitor. In the current investigation, the change in the AUC was predicted when two most commonly used drugs (Rosuvastatin and Glimepiride) were used to manage anti hyperlipidemia and diabetes. Current investigation employed the hepatic inlet concentration (determined majorly by the presence of OATP drug transporters) of Rosuvastatin which is the major rate limiting step in determining the active concentration reaching the site to elicit its therapeutic response. Alternately Glimepiride disposition is also effected by OATP transporters although at a higher affinity as shown in certain studies reported in the literature.
The results indicate a change in the rosuvastatin AUC upon long term usage of Glimepiride. However, such study need to be validated in the clinical scenario as elevated concentrations in the clinic for Rosuvastatin would precipitate the devastating Rhabdomylosis in patients who are on co-medication with the drugs under current investigation.
Keywords: Rosuvastatin, Glimepiride, Hepatic inlet concentration, OATP transporters, Cmax