Research ArticlesPropranolol Disposition in the Rat: Variation in Hepatic Extraction with Unbound Drug Fraction
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Discussions on the hepatic well-stirred model: Re-derivation from the dispersion model and re-analysis of the lidocaine data
2018, European Journal of Pharmaceutical SciencesCitation Excerpt :Blanchard et al. (2004) observed that unbound in vitro intrinsic clearance (corrected by the in vitro unbound fraction) of mibefradil, midazolam, and RO-X can be significantly different in the presence and absence of serum in hepatocyte studies. Furthermore, Gariépy et al. (1992) demonstrated that the apparent intrinsic clearances at low (fu, pf≤0.034) and high (fu, pf=0.978) unbound fractions are significantly different in an IPRL study of propranolol. Øie and Fiori (Oie and Fiori, 1985) showed that the unbound clearance of two low hepatic clearance drugs, prazosin and antipyrine, can be altered in the presence of albumin and/or AAG in IPRL studies.
In vitro-in vivo extrapolation of clearance: Modeling hepatic metabolic clearance of highly bound drugs and comparative assessment with existing calculation methods
2012, Journal of Pharmaceutical SciencesCitation Excerpt :The central issue is whether the traditional assumption for drug access to the hepatocytes holds true for IVIVE. This assumption is that equilibrium between the free and protein-bound drug is instantaneous, such that the metabolism process is driven by a constant supply of unbound drug concentration in plasma.1–9 The equilibrium model generally refers to a well-stirred or parallel tube.
Investigation of the utility of published in vitro intrinsic clearance data for prediction of in vivo clearance
2006, Journal of Pharmacological and Toxicological MethodsPrediction of pharmacokinetics prior to in vivo studies. II. Generic physiologically based pharmacokinetic models of drug disposition
2002, Journal of Pharmaceutical SciencesCitation Excerpt :It is essential to scale CLint determined in vitro to the in vivo situation. The scaling of CLint in vitro was presented as follows step-by-step: (i) providing the literature data on CLint for the disappearance clearance of each drug in fresh suspensions of rat hepatocytes (μL/min/106 cells; Table 2,12,22 (ii) scaling these in vitro data on CLint with a traditional scaling factor (109 × 106 cells/g liver)23 to estimate CLint in L/min under in vivo conditions, and (iii) calculating Eh in vivo [= CLint / (CLint + Qh)] used in the mass balance differential equation of liver. In calculating Eh, the required values of Qh and liver weight were set equal to 0.0145 L/min and 9.15 g, respectively (Table 1).