The potential protein-mediated hepatic uptake: discussion on the molecular interactions between albumin and the hepatocyte cell surface and their implications for the in vitro-to-in vivo extrapolations of hepatic clearance of drugs

ABSTRACT

Introduction: In quantitative modeling, the resolving of underpredictions and overpredictions of hepatic clearance (CLh) makes a top priority for pharmacokinetic modelers. Clearly, the ‘protein-mediated hepatic uptake’ is a violation of ‘the free drug hypothesis’, but the lack of its consideration in CLh-predictive approaches may be one of the reasons to explain the discrepancies between predicted and observed values.

Areas covered: We first review the two ‘albumin-facilitated hepatic uptake’ models that were recently challenged to improve the in vitro-to-in vivo extrapolation (IVIVE) of CLh by reducing the underprediction bias, particularly in the absence of albumin (ALB) in vitro compared to the presence of ALB in vivo. Second, we identify three types of interactions related to the ALB-bound drug moiety (i.e., ALB-lipids, ALB-proteins, and ALB-ligand allosteric interactions) that may be behind the ‘ALB-mediated hepatic uptake’ mechanism(s) for highly bound drugs. Main keywords used in our search are IVIVE; albumin; allostery; protein-mediated uptake; hepatic clearance; polarized hepatocytes.

Expert opinion: Understanding the implication of these interactions and the enzyme/transporter interplay for each drug would help selecting the appropriate IVIVE model. Therefore, we have proposed a tree of decision for guidance. The next step is to improve the ‘ALB-facilitated hepatic uptake’ models to cover the remaining uncertainties.

KEYWORDS:

• Albumin
• protein-ligand complex
• protein-mediated hepatic uptake
• pharmacokinetics
• biopharmaceutics classification system
• in vitro-to-in vivo extrapolations
• fractional plasma binding
• PBPK

Article highlights

• For the ligands that are highly bound to albumin (ALB), the bound drug moiety may also contribute to its total hepatic uptake and clearance.

• One or many process(es) may be behind the ALB-mediated hepatic uptake mechanism(s); they are grouped into three types of interactions at the molecular level: ALB-ligand allosteric interactions, ALB-lipid, and ALB–protein interactions. Hence, the presence of these three types of interactions suggests that, for particular drugs, the ALB-bound drug moiety may interact with the components of the hepatocyte plasma membrane.

• Allosteric interactions and conformational changes of ALB following the binding of a drug may change the extent of the ALB-drug complex interaction with the plasma membranes of sinusoidal hepatocytes, thus affecting the desorption/retention of the ligand in the interstitial space. These specific effects could potentially explain why, for some highly bound drugs, the ALB-bound drug moiety showed a higher degree of ALB-mediated CLh than others.

• Choosing the best IVIVE-based model would depend on the drug properties and whether ALB is added to the incubation medium in the in vitro versus the in vivo conditions.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the Natural Science and Engineering Research Council of Canada, grant no. RGPIN-2015-05577. A financial support from the Consultant Patrick Poulin Inc. (P.P.) is also acknowledged.