Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations. Sheila Annie Peters

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CYP3A4 to remain unsaturated due to the dilution effects of P‐gp efflux. The mean residence time of drug and enzyme also increases, as the drug is presented to the enzymes repeatedly while it transits down the small intestine. P‐gp efflux however, also offers a competing mechanism to metabolism both in the liver and in the gut. The roles of renal anionic and cationic transporters in drug disposition have been reviewed (Dresser et al., 2001; Masereeuw and Russel, 2010).

      For short half‐life drugs that require plasma or tissue concentrations to be maintained at the therapeutic level for a short treatment period, a constant‐rate IV infusion administered in hospital‐settings via a drip or pump offers the best solution. With a constant‐rate infusion, the rate of change in the amount of drug in plasma is the difference between the rate of drug infusion, R0, (what goes in) and its rate of elimination (what goes out). Expressing this mathematically (see Equations 1.1 and 1.2),

      (1.43)equation

      (1.44)equation

      Thus, knowing MRT and CL, the steady state volume of distribution (VSS ) of a drug can be estimated.

      (1.45)equation

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