Y Kwon1, P B Inskeep. 1. Drug Metabolism Department, Central Research Division, Pfizer Inc., Groton, Connecticut 06340, USA.
Abstract
PURPOSE: The amount of drug absorbed into portal blood after oral dosing (Dp.o,g) has been estimated using Fick's principle (Q-method), i.e., Dp.o,g = Qh x (AUCp.o,g--AUCp.o,c), where Qh is the portal blood flow rate, and AUCp.o,g and AUCp.o,c are the areas under the concentration-time curves of portal vein and systemic blood after oral dosing, respectively. However, this method may underestimate Dp.o,g, when the drug is subject to systemic intestinal elimination. An alternate equation (CL-method; Dp.o,g = CLs x AUCp.o,g) is described using a simple pharmacokinetic model, to estimate Dp.o,g in the presence of systemic intestinal elimination, where CLs is systemic clearance. METHODS: The model is composed of central, intestine and liver compartments, assuming that drug is eliminated by intestinal and/or hepatic pathways only. A comparison of both methods for estimating Dp.o,g was made using computer-simulation or experimental data of phenacetin from the literature. RESULTS: The simulation study demonstrated that the Q-method underestimated Dp.o,g in the presence of significant intrinsic intestinal clearance, compared to the CL-method. The similar results were observed using the experimental data of phenacetin. CONCLUSIONS: The CL-method can provide a better estimate of Dp.o,g, while the Q-method may underestimate Dp.o,g, when there is significant systemic intestinal elimination of drugs after oral administration. In addition, useful information for understanding the relationship between the extent of absorption and the first-pass effect by intestine and/or liver after oral dosing of drugs can be obtained from the present approach.
PURPOSE: The amount of drug absorbed into portal blood after oral dosing (Dp.o,g) has been estimated using Fick's principle (Q-method), i.e., Dp.o,g = Qh x (AUCp.o,g--AUCp.o,c), where Qh is the portal blood flow rate, and AUCp.o,g and AUCp.o,c are the areas under the concentration-time curves of portal vein and systemic blood after oral dosing, respectively. However, this method may underestimate Dp.o,g, when the drug is subject to systemic intestinal elimination. An alternate equation (CL-method; Dp.o,g = CLs x AUCp.o,g) is described using a simple pharmacokinetic model, to estimate Dp.o,g in the presence of systemic intestinal elimination, where CLs is systemic clearance. METHODS: The model is composed of central, intestine and liver compartments, assuming that drug is eliminated by intestinal and/or hepatic pathways only. A comparison of both methods for estimating Dp.o,g was made using computer-simulation or experimental data of phenacetin from the literature. RESULTS: The simulation study demonstrated that the Q-method underestimated Dp.o,g in the presence of significant intrinsic intestinal clearance, compared to the CL-method. The similar results were observed using the experimental data of phenacetin. CONCLUSIONS: The CL-method can provide a better estimate of Dp.o,g, while the Q-method may underestimate Dp.o,g, when there is significant systemic intestinal elimination of drugs after oral administration. In addition, useful information for understanding the relationship between the extent of absorption and the first-pass effect by intestine and/or liver after oral dosing of drugs can be obtained from the present approach.