The Corrected Traditional Equations for Calculation of Hepatic Clearance that Account for the Difference in Drug Ionization in Extracellular and Intracellular Tissue Water and the Corresponding Corrected PBPK Equation

Berezhkovskiy, Leonid M.

doi:10.1002/jps.22324

Cited by 56 publications

(71 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, the CL nonrenal of only 43% (3 of 7 compounds) was predicted within 2-fold if the percentage of drug bound to plasma protein exceeded or equaled 98%. Several recent mathematical models that incorporate factors such as plasma albumin to liver albumin ratio and drug ionization may improve the ability to predict hepatocyte incubations, including HepatoPac, by reducing average prediction bias, but may not entirely eliminate it (Berezhkovskiy, 2011;Hallifax and Houston, 2012;Poulin et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Meeting the Challenge of Predicting Hepatic Clearance of Compounds Slowly Metabolized by Cytochrome P450 Using a Novel Hepatocyte Model, HepatoPac

Chan

Moore³

et al. 2013

Drug Metab Dispos

134

114

View full text Add to dashboard Cite

Generating accurate in vitro intrinsic clearance data is an important aspect of predicting in vivo human clearance. Primary hepatocytes in suspension are routinely used to predict in vivo clearance; however, incubation times have typically been limited to 4-6 hours, which is not long enough to accurately evaluate the metabolic stability of slowly metabolized compounds. HepatoPac is a micropatterened hepatocyte-fibroblast coculture system that can be used for continuous incubations of up to 7 days. This study evaluated the ability of human HepatoPac to predict the in vivo clearance (CL) of 17 commercially available compounds with low to intermediate clearance (<12 ml/min per kg). In vitro half-life for disappearance of each compound was converted to hepatic clearance using the well stirred model, with and without correction for plasma protein binding. Hepatic CL, using three individual donors, was accurately predicted for 10 of 17 compounds (59%; predicted clearance within 2-fold of observed human in vivo clearance values). The accuracy of prediction increased to 76% (13 of 17 compounds) with an acceptance criterion defined as within 3-fold. When considering only low clearance compounds (<5 ml/ min per kg), which represented 10 of the 17 compounds, the accuracy of prediction was 60% within 2-fold and 90% within 3-fold. In addition, the turnover of three slowly metabolized compounds (alprazolam, meloxicam, and tolbutamide) in HepatoPac was directly compared with turnover in suspended hepatocytes. The turnover of alprazolam and tolbutamide was approximately 2-fold greater using HepatoPac compared with suspended hepatocytes, which was roughly in line with the extrapolated values (correcting for the longer incubation time and lower cell number with HepatoPac). HepatoPac, but not suspended hepatocytes, demonstrated significant turnover of meloxicam. These results demonstrate the utility of HepatoPac for prediction of in vivo hepatic clearance, particularly with low clearance compounds.

show abstract

Section: Discussionmentioning

confidence: 99%

Meeting the Challenge of Predicting Hepatic Clearance of Compounds Slowly Metabolized by Cytochrome P450 Using a Novel Hepatocyte Model, HepatoPac

Chan

Moore³

et al. 2013

Drug Metab Dispos

134

114

View full text Add to dashboard Cite

show abstract

“…2 However, this assumption does not hold for ionizable drugs because there is a pH difference between the extracellular and intracellular water (7.4 and 7.0, respectively). 11 Accordingly, in plasma and the cells, the central compartment is water where ionizable molecules are present in ionic and nonionic forms, which equilibrate with other constituents (e.g., proteins and lipids). More specifically, extracellular and intracellular water represent the site of ionizable molecules; therefore, both ionic and nonionic forms are present in this constituent.…”

Section: Ivive Calculation Methods Corrected By Berezhkovskiymentioning

confidence: 99%

“…The latter is the most commonly referenced reason because many studies have reported greater drug uptake into liver than that predicted based upon the existing models using free fraction of drug in arterial serum (i.e., fu p ). [3][4][5][6][7][8][9][10][11][12] Of the many studies that investigated this aspect, the ones investigating the impact of experimental settings on CL estimates seem to be of most importance. It has been observed that less accurate CL predictions were obtained with plasma-free and microsomal incubations as compared with those from incubations using plasma.…”

Section: Introductionmentioning

confidence: 99%

“…Such an approach should consider the impact of drug ionization in the extracellular and intracellular water. 11 Additionally, we hypothesize that the role of ionic interactions between the extracellular protein-drug complex and cell surface on the availability of drugs in hepatocytes should also be factored for highly bound drugs. 13 Together, these factors may result in differences in the unbound drug concentration between plasma and liver and hence impact the predicted CL values.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

In Vitro–In Vivo Extrapolation of Clearance: Modeling Hepatic Metabolic Clearance of Highly Bound Drugs and Comparative Assessment with Existing Calculation Methods

Poulin¹,

Kenny²,

Hop³

et al. 2012

Journal of Pharmaceutical Sciences

129

View full text Add to dashboard Cite

“…1). Of note, compared with the pH of blood (7.4), the pH of cytosol is slightly acidic (7.0-7.2) and this slight difference may play a significant role in the disposition of drugs (Berezhkovskiy, 2011;Hallifax and Houston, 2012;Poulin et al, 2012). The pH partitioning of lipophilic amines into acidic compartments is the mechanistic basis by which these drugs become highly sequestered in lysosomes.…”

Section: Introductionmentioning

confidence: 99%

Lysosomal Sequestration (Trapping) of Lipophilic Amine (Cationic Amphiphilic) Drugs in Immortalized Human Hepatocytes (Fa2N-4 Cells)

et al. 2013

View full text Add to dashboard Cite

Lipophilic (logP > 1) and amphiphilic drugs (also known as cationic amphiphilic drugs) with ionizable amines (pK a > 6) can accumulate in lysosomes, a process known as lysosomal trapping. This process contributes to presystemic extraction by lysosome-rich organs (such as liver and lung), which, together with the binding of lipophilic amines to phospholipids, contributes to the large volume of distribution characteristic of numerous cardiovascular and central nervous system drugs. Accumulation of lipophilic amines in lysosomes has been implicated as a cause of phospholipidosis. Furthermore, elevated levels of lipophilic amines in lysosomes can lead to high organ-to-blood ratios of drugs that can be mistaken for active drug transport. In the present study, we describe an in vitro fluorescence-based method (using the lysosome-specific probe LysoTracker Red) to identify lysosomotropic agents in immortalized hepatocytes (Fa2N-4 cells). A diverse set of compounds with various physicochemical properties were tested, such as acids, bases, and zwitterions. In addition, the partitioning of the nonlysosomotropic atorvastatin (an anion) and the lysosomotropics propranolol and imipramine (cations) were quantified in Fa2N-4 cells in the presence or absence of various lysosomotropic or nonlysosomotropic agents and inhibitors of lysosomal sequestration (NH 4 Cl, nigericin, and monensin). Cellular partitioning of propranolol and imipramine was markedly reduced (by at least 40%) by NH 4 Cl, nigericin, or monensin. Lysosomotropic drugs also inhibited the partitioning of propranolol by at least 50%, with imipramine partitioning affected to a lesser degree. This study demonstrates the usefulness of immortalized hepatocytes (Fa2N-4 cells) for determining the lysosomal sequestration of lipophilic amines.

show abstract

The Corrected Traditional Equations for Calculation of Hepatic Clearance that Account for the Difference in Drug Ionization in Extracellular and Intracellular Tissue Water and the Corresponding Corrected PBPK Equation

Cited by 56 publications

References 58 publications

Meeting the Challenge of Predicting Hepatic Clearance of Compounds Slowly Metabolized by Cytochrome P450 Using a Novel Hepatocyte Model, HepatoPac

Meeting the Challenge of Predicting Hepatic Clearance of Compounds Slowly Metabolized by Cytochrome P450 Using a Novel Hepatocyte Model, HepatoPac

In Vitro–In Vivo Extrapolation of Clearance: Modeling Hepatic Metabolic Clearance of Highly Bound Drugs and Comparative Assessment with Existing Calculation Methods

Lysosomal Sequestration (Trapping) of Lipophilic Amine (Cationic Amphiphilic) Drugs in Immortalized Human Hepatocytes (Fa2N-4 Cells)

Contact Info

Product

Resources

About