P20 WHEN DOES THE RATE-DETERMINING STEP IN HEPATIC CLEARANCE OF A DRUG SWITCH FROM SINUSOIDAL UPTAKE CLEARANCE TO ALL HEPATOBILIARY CLEARANCES?

Gabriela Patilea-Vrana , Pharmaceutics, University of Washington, Seattle, WA
Jashvant D. Unadkat , University of Washington, Seattle, WA
In drug development, it is important to identify the rate-determining step in the clearance of drugs. With respect to hepatic clearance, this can be the sinusoidal uptake clearance (CLsin), metabolic clearance (CLmet), biliary clearance (CLcef), or all three clearances. If CLsin is the rate-determining step in hepatic clearance, inhibition of CLmet, CLcef, or both will not affect systemic clearance of the drug but will profoundly increase the hepatic concentration and AUC (and therefore the hepatic efficacy/toxicity) of the drug. CLsin is the rate-determining step when CLmet + CLcef >> CLsef (sinusoidal efflux clearance). When this condition is no longer met, inhibition of CLmet, CLcef, CLsin, or all three will result in significant increase to the systemic AUC because the rate-determining step in hepatic clearance of the drug has switched from CLsin to all hepatobiliary clearances. Thus, it is important to identify condition(s) when this switch happens. Through theoretical simulations (MATLAB) we determined the minimum ratio of CLmet + CLcef and CLsef needed to maintain CLsin as the rate-determining step, hereafter referred to as the tipping point. First, we established that the tipping point is independent of the absolute value of CLmet, CLcef, or CLsef and is dependent only on the ratio of CLmet + CLcef and CLsef. Next, we demonstrated that as CLsin increases, the tipping point decreases. For example, when CLsin is 0.25-times and 4-times the hepatic blood flow (equivalent to a hepatic extraction ratio (ER) of 0.2 and 0.8, respectively), the tipping point is 4 and 1, respectively. For any ratio of CLmet + CLcef and CLsef, we identified the maximum % inhibition of CLmet + CLcef before the tipping point is reached and the rate-determining step in hepatic clearance of the drug switches from CLsin to all hepatobiliary clearances. For example, for a drug with CLmet + CLcef and CLsef ratio of 5 and ER of 0.2 and 0.8, CLmet + CLcef can be inhibited a maximum of 10% and 82%, respectively, before hepatic clearance switches from depending on only CLsin to depending on all hepatobiliary clearance pathways. Alternatively, for any % inhibition of CLmet + CLcef, we identified what is the minimum ratio of CLmet + CLcef required to maintain CLsin as the rate-determining step. For example, for a drug where CLmet + CLcef is inhibited by 50%, a minimum ratio of CLmet + CLcef and CLsef of 9.1 and 1.9 is required to maintain CLsin as the rate-determining step for when the ER is 0.2 and 0.8, respectively. Overall, through theoretical simulations we have elucidated the tipping point at which the rate-determining step in hepatic clearance of drugs switches from CLsin to all hepatobiliary clearance pathways and the conditions needed to maintain CLsin as the rate-determining step. These simulations provide a framework to predict the site of drug interactions when a drug is cleared by transporters and metabolism/biliary excretion.

Supported by NCATS Grant TL1 TR000422 and NIDA Grant P01DA032507.