Although the liver is the major site for drug biotransformation, the effect of hepatic dysfunction on drug disposition has not been consistent or predictable. Most early studies of drug kinetics in liver disease measured only half-life. Only in the past few years has it been realised that liver diseases can affect drug absorption, hepatic metabolism, tissue distribution, and protein binding, which complicate interpretation of any change, or lack of change in drug half-life. Furthermore, it is now apparent that the efficiency with which a drug is metabolised by the liver, the extent of binding to blood constituents, and the aetiology and stage of the hepatic disorder are each important in determining whether significant alterations in drug disposition will occur. A pharmacokinetic perfusion model which takes into account many of the above factors has been proposed, and appears to be useful for predicting changes in the disposition of rapidly metabolised compounds. Nevertheless, the state of knowledge about those factors which limit the rate of metabolism of individual drugs or classes of drugs is inadequate, and no general model or guidelines which are useful clinically have been developed. Patients with hepatic disorders may show increases or decreases in sensitivity independent of alterations in drug disposition. The clinician caring for such patients must be cautious about the use of any drugs, and rely heavily on careful patient observation to determine efficacy or toxicity.

Protein Binding and Kinetics of Drugs in Liver Diseases

Systemic toxicity testing forms the cornerstone for the safety evaluation of substances. Pressures to move from traditional animal models to novel technologies arise from various concerns, including: the need to evaluate large numbers of previously untested chemicals and new products (such as nanoparticles or cell therapies), the limited predictivity of traditional tests for human health effects, duration and costs of current approaches, and animal welfare considerations. The latter holds especially true in the context of the scheduled 2013 marketing ban on cosmetic ingredients tested for systemic toxicity. Based on a major analysis of the status of alternative methods (Adler et al., 2011) and its independent review (Hartung et al., 2011), the present report proposes a roadmap for how to overcome the acknowledged scientific gaps for the full replacement of systemic toxicity testing using animals. Five whitepapers were commissioned addressing toxicokinetics, skin sensitization, repeated-dose toxicity, carcinogenicity, and reproductive toxicity testing. An expert workshop of 35 participants from Europe and the US discussed and refined these whitepapers, which were subsequently compiled to form the present report. By prioritizing the many options to move the field forward, the expert group hopes to advance regulatory science.

/pdf/a-roadmap-for-the-development-of-alternative-non-animal-35m1hr1jow.pdf

A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing.

For some drugs, delivery to the liver by the hepatic circulation is an important determinant of removal by this organ. Classical pharmacokinetic analyses cannot predict the changes produced by altering any of the biological determinants of drug elimination by the liver; hepatic blood flow, metabolic enzyme activity, drug binding and route of administration. However, with the use of a physiological model of hepatic drug elimination, such predictions can be made. This model has been tested experimentally and appears to be valid. Hepatic blood flow can vary over about a 4-fold range from half normal flow to twice normal flow. These variations are produced by physiological, pathological or pharmacological changes affecting the circulation. For drug clearance to be affected significantly by these changes in flow, the drug must be avidly removed by the liver as reflected in a high hepatic extraction ratio and intrinsic hepatic clearance. This latter term is a useful way to characterise the ability of the liver to irreversibly remove drug from the circulation in the absence of any flow limitation. The clearance of drugs with low intrinsic clearances will not be affected significantly by changes in liver blood flow.

Altered hepatic blood flow and drug disposition.

The field of toxicology is currently undergoing a global paradigm shift to use of in vitro approaches for assessing the risks of chemicals and drugs in a more mechanistic and high throughput manner than current approaches relying primarily on in vivo testing. However, reliance on in vitro data entails a number of new challenges associated with translating the in vitro results to corresponding in vivo exposures. Physiologically based pharmacokinetic (PBPK) modeling provides an effective framework for conducting quantitative in vitro to in vivo extrapolation (QIVIVE). Their physiological structure facilitates the incorporation of in silico- and in vitro-derived chemical-specific parameters in order to predict in vivo absorption, distribution, metabolism and excretion. In particular, the combination of in silico- and in vitro parameter estimation with PBPK modeling can be used to predict the in vivo exposure conditions that would produce chemical concentrations in the target tissue equivalent to the concentr...

Quantitative in vitro to in vivo extrapolation of cell-based toxicity assay results.

Multiple hepatic P450 enzymes play an important role in the oxidative biotransformation of a vast number of structurally diverse drugs. As such, these enzymes are a major determinant of the pharmacokinetic behaviour of most therapeutic agents. There are several factors that influence P450 activity, either directly or at the level of enzyme regulation. Drug elimination is decreased and the incidence of drug interactions is increased when there is competition between 2 or more drugs for oxidation by the same P450 enzyme. The available knowledge concerning the relationship between the presence of certain functional groups within the drug structure and inhibition of P450 activity is increasing. In many instances, it is possible to associate inhibition with certain drug classes, e.g. antimycotic imidazoles and macrolide antibiotics. Disease states, especially those with hepatic involvement, and the genetic makeup of the individual are conditions in which some P450s may be downregulated (that is, the enzyme concentrations in liver are decreased), with associated slower rates of drug elimination. In these individuals, dosages of drugs that are substrates for downregulated P450s should be decreased. Exposure to environmental pollutants as well as a large number of lipophilic drugs can result in induction (upregulation) of P450 enzyme activity. This raises the issue of previous approaches to the study of P450 induction in vivo. The use of human hepatocyte preparations in culture is a promising new direction that could assist the determination of modifications to drug therapy necessitated by exposure to inducing agents. Until such information is obtained, however, the use of drugs known to increase the microsomal expression of particular P450s, and increase associated drug oxidation capacity in humans, should be used with caution.

S. Schenker

Papers

Drug Disposition and Liver Disease