Showing papers in "Expert Opinion on Drug Metabolism & Toxicology in 2008"

Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily.

Abstract: Background: Aldehydes are highly reactive molecules. While several non-P450 enzyme systems participate in their metabolism, one of the most important is the aldehyde dehydrogenase (ALDH) superfamily, composed of NAD(P)+-dependent enzymes that catalyze aldehyde oxidation. Objective: This article presents a review of what is currently known about each member of the human ALDH superfamily including the pathophysiological significance of these enzymes. Methods: Relevant literature involving all members of the human ALDH family was extensively reviewed, with the primary focus on recent and novel findings. Conclusion: To date, 19 ALDH genes have been identified in the human genome and mutations in these genes and subsequent inborn errors in aldehyde metabolism are the molecular basis of several diseases, including Sjogren-Larsson syndrome, type II hyperprolinemia, γ-hydroxybutyric aciduria and pyridoxine-dependent seizures. ALDH enzymes also play important roles in embryogenesis and development, neurotransmissi...

The Caco-2 cell monolayer: usefulness and limitations

Abstract: Background: The Caco-2 monolayer has been used extensively for the high-throughput screening of drug permeability and identification of substrates, inhibitors, and inducers of intestinal transporters, especially P-glycoprotein (P-gp). Traditionally, the Caco-2 monolayer is viewed as a single barrier rather than a polarized cell monolayer consisting of metabolic enzymes that are sandwiched between two membrane barriers with distinctly different transporters. Objective: This review addressed the usefulness and limitations of the Caco-2 cell monolayer in drug discovery and mechanistic studies. Methods: This mini-review covered applications of the Caco-2 monolayer, clarified misconceptions, and critically addressed issues on data interpretation. Conclusion: The catenary model extends the usefulness of Caco-2 monolayer and provides proper mechanistic insight and data interpretation.

Development of inhibitors of ATP-binding cassette drug transporters – present status and challenges

Abstract: Background: Multi-drug resistance (MDR) of cancer cells is an obstacle to effective chemotherapy of cancer. The ATP-binding cassette (ABC) transporters, including P-glycoprotein (ABCB1), MRP1 (ABCC1) and ABCG2, play an important role in the development of this resistance. An attractive approach to overcoming MDR is the inhibition of the pumping action of these transporters. Several inhibitors/modulators of ABC transporters have been developed, but cytotoxic effects and adverse pharmacokinetics have prohibited their use. The ongoing search for such inhibitors/modulators that can be applied in the clinic has led to three generations of compounds. The most recent inhibitors are more potent and less toxic than first-generation compounds, yet some are still prone to adverse effects, poor solubility and unfavorable changes in the pharmacokinetics of the anticancer drugs. Objective: This review provides an update of the published work on the development of potent modulators to overcome MDR in cancer cells, their...

The effect of chronic renal failure on drug metabolism and transport

Abstract: Background: Chronic renal failure (CRF) has been shown to significantly reduce the nonrenal clearance and alter bioavailability of drugs predominantly metabolized by the liver and intestine. Objectives: The purpose of this article is to review all significant animal and clinical studies dealing with the effect of CRF on drug metabolism and transport. Methods: A search of the National Library of Medicine PubMed was done with terms such as chronic renal failure, cytochrome P450 [CYP], liver metabolism, efflux drug transport and uptake transport, including relevant articles back to 1969. Results: Animal studies in CRF have shown a significant downregulation (40 – 85%) of hepatic and intestinal CYP metabolism. High levels of parathyroid hormone, cytokines and uremic toxins have been shown to reduce CYP activity. Phase II reactions and drug transporters such as P-glycoprotein and organic anion transporting polypeptide are also affected. Conclusion: CRF alters intestinal, renal and hepatic drug metabolism and t...

Neuroinflammation and microglia: considerations and approaches for neurotoxicity assessment

Abstract: Background—The impact of an inflammatory response, as well as interactions between the immune and nervous systems, are rapidly assuming major roles in neurodegenerative disease and injury. However, it is now appreciated that the exact nature of such responses can differ with each type of insult and interaction. More recently, neuroinflammation and the associated cellular response of microglia are being considered for their contribution to neurotoxicity of environmental agents; yet, to date, the inclusion of inflammatory endpoints into neurotoxicity assessment have relied primarily on relatively limited measures or driven by in vitro models of neurotoxicity. Objective—To present background information on relevant biological considerations of neuroinflammation and the microglia response demonstrating the complex integrative nature of these biological processes and raising concern with regards to translation of effects demonstrated in vitro to the in vivo situation. Specific points are addressed that would influence the design and interpretation of neuroinflammation with regards to neurotoxicology assessment. Conclusion—There is a complex and dynamic response in the brain to regulate inflammatory processes and maintain a normal homeostatic level. The classification of such responses as beneficial or detrimental is an oversimplification. Neuroinflammation should be considered as a balanced network of processes where subtle modifications can shift the cells toward disparate outcomes. The tendency to over-interpret data obtained in an isolated culture system should be discouraged. Rather, the use of cross-disciplinary approaches to evaluate multiple endpoints should be incorporated into the assessment of inflammatory contributions to the neurotoxicity of environmental exposures.

ABCG2: structure, function and role in drug response

Abstract: ABCG2 was discovered in multi-drug-resistant cancer cells, with the identification of chemotherapeutic agents, such as mitoxantrone, flavopiridol, methotrexate and irinotecan as substrates. Later, drugs from other therapeutic groups were also described as substrates, including antibiotics, antivirals, HMG-CoA reductase inhibitors and flavonoids. An expanding list of compounds inhibiting ABCG2 has also been generated. The wide variety of drugs transported by ABCG2 and its normal tissue distribution with highest levels in the placenta, intestine and liver, suggest a role in protection against xenobiotics. ABCG2 also has an important role in the pharmacokinetics of its substrates. Single nucleotide polymorphisms of the gene were shown to alter either plasma concentrations of substrate drugs or levels of resistance against chemotherapeutic agents in cell lines. ABCG2 was also described as the determinant of the side population of stem cells. All these aspects of the transporter warrant further research aimed at understanding ABCG2's structure, function and regulation of expression.

In vitro models of the human epithelial airway barrier to study the toxic potential of particulate matter.

Abstract: Background: Several epidemiological studies show that inhalation of particulate matter may cause increased pulmonary morbidity and mortality. Of particular interest are the ultrafine particles that...

Intestinal efflux transporters and drug absorption.

Abstract: Background: The intestinal epithelial membrane expresses ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), multi-drug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP), in addition to various solute carrier (SLC) transporters. These ABC transporters affect the oral bioavailability of their substrate drugs. Objective: To review the contribution of ABC efflux transporters such as P-gp, MRP2, MRP3, and BCRP in the intestinal absorption of substrate drugs. Methods: Discussion was made by focusing on the site-specific expression and function of these ABC transporters, and the solubility and permeability of their substrate compounds. Results/conclusion: The increase in the solubility and permeability of orally administered drugs could be the key to escape barrier function of ABC transporters, especially P-gp.

The influence of circadian rhythms on the kinetics of drugs in humans

Abstract: In clinical practice, it is important to consider circadian rhythms in pharmacokinetics and cell responses to therapy in order to design proper protocols for drug administration. Scientists have arrived at this conclusion after several experiments in animals and in humans have clearly demonstrated that all organisms are highly organised according to circadian rhythms. These temporal cycles influence different physiological functions and, consequently, can influence the pharmacokinetic phases of drugs. A drug's pharmacokinetics can be modified according to the time of drug administration. In fact, the circadian changes of > 100 different compounds have been documented. The results obtained have led several scientific societies to provide guidelines concerning the timing of drug dosing for anticancer, cardiovascular, respiratory, anti-ulcer, anti-inflammatory, immunosuppressive and antiepileptic drugs. Absorption may be influenced by circadian rhythms and most lipophilic drugs seem to be absorbed faster when the drug is taken in the morning compared with the evening; for water-soluble compounds, no circadian variation in the absorption of drugs has been found. Concerning drug distribution, the higher the blood flow fraction an organ receives, the higher the rate constant for transferring drugs out of the capillaries. This drug pharmacokinetic phase may be influenced by circadian variations in the protein binding of acidic and basic drugs. Drug metabolism may be influenced by daily modifications of blood flow. For drugs with a high extraction ratio, metabolism depends on hepatic blood flow, while that of drugs with a low extraction ratio depends on liver enzyme activity. Hepatic blood flow has been shown to be greatest at 8 am and metabolism seems to be reduced during the night. Finally, concerning drug elimination, the clearance of 'flow-limited' drugs that present a high extraction rate is affected by the blood flow delivered to the organ, independent of the cardiac output fraction supplied. Chronopharmacokinetics can explain individual differences in drug levels revealed by therapeutic drug monitoring and can be used to optimise the management of patients receiving drug therapy.

Sex-specific differences in CYP450 isoforms in humans

Abstract: Background: The activity of various CYP isoforms is critical for maintaining the clinical effectiveness of many medications. Therefore, determining the sex-dependent activity of clinically relevant CYP families is highly important for optimal therapeutic effectiveness. Objective: This review examined the sex-dependent activity of CYP3A, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP2E1. Methods: This review searched for studies performed in humans and hormonal status was not a limiting factor. Results/conclusions: The current evidence suggests that CYP2E1 and CYP1A2 activity is higher in males than females, while CYP3A, one of the most clinically relevant CYP isoforms, appears to have greater activity in females. Overall, more studies are needed to fully support these conclusions as there are many factors that influence drug metabolism and thus it is very difficult to isolate gender as a sole modulator of CYP activity.

Dexmedetomidine: sedation, analgesia and beyond.

Abstract: Background: Dexmedetomidine is an α-2 adrenoreceptor agonist with sedative, analgesic and anxiolytic properties. Since its release in the US market in late 1999, it has gained remarkable attention in the adult, pediatric and geriatric populations, predominantly because of its minimal respiratory depression. However, beyond its well-known properties, dexmedetomidine has recently been investigated for its potential in many other clinical scenarios, including neuroprotection, cardioprotection and renoprotection, with promising results. Objective: This review provides an outline of the current use of dexmedetomidine in adult and pediatric populations in several clinical settings, including operating room, intensive care unit, postsurgical patients and patients who need sedation and/or analgesia for invasive and noninvasive procedures. Our objectives were to examine the most up-to-date clinical evidence, describe the magnitude of effects, and shed some light on potential future applications. Methods: Published...

Ambroxol in the 21st century: pharmacological and clinical update

Abstract: Background: Belonging to the group of expectorants, ambroxol is an active substance with a long history that influences parameters considered to be the basis for the physiological production and the transport of the bronchial mucus. Therefore, ambroxol's indication is ‘secretolytic therapy in acute and chronic bronchopulmonary diseases associated with abnormal mucus secretion and impaired mucus transport’. Objective: The aim of this review is to evaluate the pharmacological and clinical data on the mucokinetic compound ambroxol. Methods: The existing database that covers > 40 years of pharmacological research and clinical development was analysed. Only studies with adequate study design were evaluated. Conclusion: Ambroxol is shown to exert several activities: i) secretolytic activity (i.e., promotes mucus clearance, facilitates expectoration, and eases productive cough); ii) anti-inflammatory and antioxidant activity; and iii) a local anaesthetic effect through sodium channel blocking at the level of the...

Evolving concepts in liver tissue modeling and implications for in vitro toxicology.

Abstract: The development of human cell models stably expressing functional properties of the in vivo cells they are derived from for predicting toxicity of chemicals is a major challenge. For mimicking the liver, a major target of toxic chemicals, primary hepatocytes represent the most pertinent model. Their use is limited by interdonor functional variability and early phenotypic changes although their lifespan can be extended not only by culturing in a 2D dimension under sophisticated conditions but also by the use of synthetic and natural scaffolds as 3D supporting templates that allow cells to have a more stable microenvironment. Hepatocytes derived from stem cells could be the most appropriate alternative but up to now only liver progenitors/hepatoblasts are obtained in vitro. A few hepatocyte cell lines have retained a variable set of liver-specific functions. Among them are the human hepatoma HepaRG cells that express drug metabolism capacity at levels close to those found in primary hepatocytes making them a suitable model for both acute and chronic toxicity studies. New screening strategies are now proposed based on miniaturized and automated systems; they include the use of microfluidic chips and cell chips coupled with high content imaging analysis. Toxicogenomics technologies (particularly toxicotranscriptomics) have emerged as promising in vitro approaches for better identification and discrimination of cellular responses to chemicals. They should allow to discriminate compounds on the basis of the identification of a set of markers and/specific signaling pathways.

Metabolic activation of carboxylic acids.

Abstract: Background: Carboxylic acids constitute a large and heterogeneous class of both endogenous and xenobiotic compounds. A number of carboxylic acid drugs have been associated with adverse reactions, linked to the metabolic activation of the carboxylic acid moiety of the compounds, i.e., formation of acyl-glucuronides and acyl-CoA thioesters. Objective: The objective is to give an overview of the current knowledge on metabolic activation of carboxylic acids and how such metabolites may play a role in adverse reactions and toxicity. Methods: Literature concerning the formation and disposition of acyl glucuronides and acyl-CoA thioesters was searched. Also included were papers on the chemical reactivity of acyl glutathione-thioesters, and literature concerning possible links between metabolic activation of carboxylic acids and reported cellular and clinical effects. Results/conclusion: This review demonstrates that metabolites of carboxylic acid drugs must be considered chemically reactive, and that the current...

Whole body physiologically-based pharmacokinetic models: their use in clinical drug development

Abstract: Background: Whole-body physiologically-based pharmacokinetic (WB-PBPK) models mathematically describe an organism as a closed circulatory system consisting of compartments that represent the organs important for compound absorption, distribution, metabolism and elimination. Objectives: To review the current state of WB-PBPK model use in the clinical phases of drug development. Methods: A qualitative description of the WB-PBPK model structure is included along with a review of the varying methods available for input parameterisation. Current and potential WB-PBPK model application in clinical development is discussed. Conclusions: This modelling tool is at present used for small and large molecule drug development primarily as a means to scale pharmacokinetics from animals to humans based on physiology. The pharmaceutical industry is active in employing these models to clinical drug development although the applications in use now are narrow in comparison to the potential. Expanded integration of WB-PBPK m...

Application of dendrimer-drug complexation in the enhancement of drug solubility and bioavailability.

Abstract: Dendrimers are 3D, hyperbranched, tree-like polymers having immense potential in drug delivery, targeting, diagnosis and as carriers for DNA/gene delivery. Dendrimers have hydrophilic exteriors and...

Interplay of conjugating enzymes with OATP uptake transporters and ABCC/MRP efflux pumps in the elimination of drugs

Abstract: Background: Biliary excretion is a major elimination route of many drugs and their metabolites. Hepatobiliary elimination is a vectorial process involving uptake transporters in the basolateral hepatocyte membrane, possibly Phase I and Phase II metabolizing enzymes, and ATP-dependent efflux pumps in the apical hepatocyte membrane. Objectives: Because many drugs and their metabolites are anions, this review focuses on transporters involved in their hepatocellular uptake (members of the organic anion transporting polypeptide (OATP) family) and biliary elimination (apical conjugate efflux pump ABCC2/MRP2). Methods: The molecular and functional characteristics of the human OATP and ABCC/MRP transporters are presented, including a detailed overview of endogenous and drug substrates. Examples illustrate the interplay of transporters with Phase II conjugating enzymes. Model systems to study the vectorial transport of organic anions are also discussed. Results/conclusions: OATP uptake transporters, conjugating en...

Allosteric P450 mechanisms: multiple binding sites, multiple conformers or both?

Abstract: According to the initial hypothesis on the mechanisms of cooperativity in drug-metabolizing cytochromes P450, a loose fit of a single substrate molecule in the P450 active site results in a requirement for the binding of multiple ligand molecules for efficient catalysis. Although simultaneous occupancy of the active site by multiple ligands is now well established, there is increasing evidence that the mechanistic basis of cooperativity also involves an important ligand-induced conformational transition. Moreover, recent studies demonstrate that the conformational heterogeneity of the enzyme is stabilized by ligand-dependent interactions of several P450 molecules. Application of the concept of an oligomeric allosteric enzyme to microsomal cytochromes P450 in combination with a general paradigm of multiple ligand occupancy of the active site provides an excellent explanation for complex manifestations of the atypical kinetic behavior of the enzyme.

The Pregnane X Receptor: From Bench to Bedside

Abstract: Background: The pregnane X receptor (PXR; NR1I2), a member of the nuclear receptor superfamily, regulates the expression of metabolic enzymes and transporters involved in the response of mammals to their chemical environment. Objective: To summarize the functions and clinical implications of PXR. Methods: In the current review, the clinical implications of PXR are discussed, and the use of genetically engineered PXR mouse models is highlighted. Results/conclusion: Recent advances in mouse models, including Pxr-null and PXR-humanized mice, provide in vivo tools for evaluating the physiological functions of PXR and its role in controlling xenobiotic metabolism and transport. By using the PXR knockout and humanized mouse models, PXR was found to influence drug–drug interactions, hepatic steatosis, and the homeostasis of vitamin D, bile acids, and steroid hormones. PXR was also shown to influence inflammatory bowel diseases.

Potential role of intestinal first-pass metabolism in the prediction of drug-drug interactions.

Abstract: Background: The contribution of intestine to the magnitude of drug–drug interactions (DDI) may be significant, considering high levels of inhibitors in the gut lumen achieved during absorption and the abundance of metabolic enzymes in the mature enterocytes. Intestinal inhibition is incorporated in the DDI prediction models as the ratio of the intestinal wall availability in the presence and absence of the inhibitor (FG′ and FG, respectively). Objective: This review will focus on the ability of the current approaches to estimate the extent of intestinal DDI accurately, addressing predominantly the most abundant intestinal P450 enzyme, CYP3A4. Methods: Considering the sensitivity of the DDI prediction models to the accuracy of the FG estimates, the current study focuses on 3 different in vitro and in vivo approaches to assess this parameter. Results/conclusion: The advantages and limitations of each of FG methods are outlined. Accurate assessment of this parameter is essential for the prediction of human d...

Structure – ADME relationship: still a long way to go?

Abstract: Background: Theoretical models for predicting absorption, distribution, metabolism and excretion (ADME) properties play increasingly important roles in support of the drug development process. Objective: We briefly review the in silico prediction models for three important ADME properties, namely, aqueous solubility, human intestinal absorption, and oral bioavailability. Methods: Rather than giving detailed descriptions of the ADME prediction models, we focus on the discussions of the prediction accuracies of the in silico models. Results/conclusion: We find that the robustness and predictive capability of the ADME models are directly associated with the complexity of the ADME property. For the ADME properties involving complex phenomena, such as bioavailability, the in silico models usually cannot give satisfactory predictions. Moreover, the lack of large and high-quality data sets also greatly hinder the reliability of ADME predictions. While considerable progress has been achieved in ADME predictions, ...

Effect of dietary flavonoids on pathways involved in drug metabolism.

Abstract: Flavonoids are a large group of plant polyphenols with presumed beneficial effects on several common diseases. The use of dietary supplements enriched with flavonoids is becoming increasingly popular. These polyphenols are substrates of enzymes like cytochrome P450 monooxygenases and phase II conjugation enzymes, as well as of drug transporters involved in drug excretion. Thus, they share the same metabolic pathways with many therapeutic drugs. A number of studies have demonstrated inhibition of various cytochrome P450 monooxygenases and drug transporters by flavonoids. Flavonoid-induced effects on drug bioavailability were also shown. This raises concerns about the safe use of flavonoid supplements and flavonoid-containing remedies which are not subject to legal regulations. The challenge is to find a suitable way to predict harmful drug-flavonoid interactions.

In vitro cell culture models for the assessment of pulmonary drug disposition.

Abstract: Background: Aerosol administration of therapeutics to the respiratory system represents a significant opportunity for many classes of drugs, both small molecules and macromolecules, including recently engineered peptide and protein therapeutics. However, minimally invasive assessment of drug absorption mechanisms in vivo or from the isolated organ is prevented by the complex architecture of the lung. Thus, cell culture models of the bronchial and alveolar epithelial barriers have been developed for absorption mechanisms studies and are now widely used as in vitro screening tools. Objectives: The aim of this article is to provide an update of the published work on various in vitro models of respiratory epithelium while emphasising the advantages and limitations of each model. Methods: This review summarises recent advances in the development and characterisation of in vitro cell culture models for drug disposition studies. Conclusions: A variety of cell culture systems for modelling the respiratory epithel...

Irregular gastrointestinal drug absorption in Parkinson's disease.

Abstract: Background Symptomatic treatment of Parkinson's disease (PD) is based on the dopamine precursor levodopa. Levodopa is only absorbed in the small intestine, where transit time is approximately 3 h and the plasma elimination half-life is short. Therefore, gastric emptying is a major determining factor for onset of symptom relief. Objective Gastric emptying is delayed in PD, thereby causing motor fluctuations such as 'delayed on'. Factors that further slow gastric emptying should be recognised and eliminated if possible. Methods A literature search was performed with the aim to cover the area of irregular gastrointestinal drug absorption in PD. Results/conclusion Methods for facilitation of pyloric passage or increase of bioavailability are discussed. Development of new drug formulations and alternative routes of administration is ongoing. Transdermal patches and pumps for subcutaneous or intraduodenal infusions are available for patients with severe fluctuations due to erratic gastric emptying.

The utility of microdosing over the past 5 years.

Abstract: Background: Microdosing studies (human Phase 0) are used to select drug candidates for Phase I clinical trials on the basis of their pharmacokinetic properties, using subpharmacologic doses (maximum 100 μg). There are questions as to whether pharmacokinetic data obtained at these low doses will predict those at the clinically relevant dose. Objective: To review the current literature on microdosing and assess how well microdose data have predicted the pharmacokinetics obtained at a therapeutic dose. Methods: All data published in the peer reviewed literature comparing pharmacokinetics at a microdose with a therapeutic dose were reviewed, excluding those studies aimed at imaging. Conclusions: Of the 18 drugs reported, 15 demonstrated linear pharmacokinetics within a factor of 2 between a microdose and a therapeutic dose. Therefore, data that support the utility of microdosing are beginning to emerge.

Riluzole in psychiatry: a systematic review of the literature.

Abstract: Background: The glutamate system seems to be an important contributor to the pathophysiology of mood and anxiety disorders. Thus, glutamatergic modulators are reasonable candidate drugs to test in patients with mood and anxiety disorders. Riluzole, a neuroprotective agent with anticonvulsant properties approved for the treatment of amyotrophic lateral sclerosis (ALS) is one such agent. Objective: To assess the potential risks and benefits of riluzole treatment in psychiatric patients. Methods: A PubMed search was performed using the keywords ‘riluzole’, ‘inhibitor of glutamate release’ and ‘glutamatergic modulator’ to identify all clinical studies and case reports involving riluzole in psychiatric patients. Results/conclusion: Riluzole's side effect profile is favorable and preliminary results regarding riluzole for the treatment of severe mood, anxiety and impulsive disorders are encouraging.

Utilization of membrane vesicle preparations to study drug-ABC transporter interactions.

Abstract: Background: The last 15 years have marked an expansion in our understanding of how ABC transporters modulate the pharmacokinetic properties of drugs. Assays based on different membrane preparations were one of the first methods developed to study ABC transporters. Later, they turned out to be valuable tools to gain insight into the nature of drug–ABC transporter interactions. Objectives: Membranes prepared from different sources have been used and characterized; based on the biochemical characteristics of the transport process, a number of different assay types have been developed. Methods: This review focuses on the current experiences on how different membrane-based assays can be utilized in pharmaceutical R&D. Sources of membrane preparations, available assay types and correlation studies between different in-vitro and in-vivo methods are discussed. Results/conclusion: Membrane-based assays are valuable tools in drug discovery to characterize drug–ABC transporter interactions.

Inflammation and CYP3A4-mediated drug metabolism in advanced cancer: impact and implications for chemotherapeutic drug dosing

Abstract: Background: The inability to accurately predict treatment outcomes for cancer patients in terms of tumour response and anticancer drug toxicity is a severe limitation inherent in current approaches to chemotherapy. Many anticancer drugs are metabolically cleared by cytochrome P450 3A4 (CYP3A4), the predominant CYP expressed in liver. CYP3A4 expression exhibits marked interindividual variation and is repressed in acute inflammatory states. Objectives: (1) To review the relevance of CYP3A4 variability to drug metabolism in the setting of cancer and to understand how inflammation associated with malignancy contributes to both this variability and to adverse treatment outcomes. (2) To examine the relationship between tumour-induced inflammation and repression of CYP3A4 and to explore methods of dosing of anticancer drugs in the setting of advanced cancer. Methods: Review of relevant literature covering both human and animal studies as well as in vitro mechanistic studies. Results/conclusions: Interindividual ...

In vitro lipid digestion models in design of drug delivery systems for enhancing oral bioavailability.

Abstract: This review focuses on recent progress in the in vitro lipid digestion models and how these models can underpin in vitro–in vivo correlations which are a key element for drug development. A plethora of articles are dealing with development of lipid-based formulations of poorly soluble compounds for oral administration; however, most studies base formulation development and proof of concept on bioavailability studies and do not consider the use of in vitro studies. A major challenge is the development of in vitro models simulating the gastric or intestinal fluids to assess their in vivo performance. The use of in vitro lipolysis models has been proposed as an approach to probe solubilisation in the aqueous phase during the progress of enzymatic degradation of lipid based-formulations. Moreover, the in vitro digestion models, coupled with biophysical methods, offer insights into the mechanisms underlying lipid digestion, by characterising the generated intermediate colloidal phases, and thereby can serve as...

The role of hepatic transporters in drug elimination

Abstract: Background: Hepatic drug transporters of the solute carrier (OATPs, OAT2, OCT1, NTCP) and ABC transporter superfamilies (MDR1, MRPs, BCRP, BSEP) can significantly modulate drug ADME routes. Objective: The currently available literature was reviewed with focus on hepatic drug transporters, related drug–drug interactions and available tools for transporter assessment and extrapolation to in vivo. Conclusions: Hepatic drug transporters have gained additional importance in drug clearance by optimization for basic DMPK properties early on in drug research. However, the lack of selective substrates and inhibitors, proper assessment of the kinetic properties due to interfering passive permeability and multiple binding sites, as well as endogenous transporters present in many cellular assays, are some of the hurdles in studying active drug transport processes. Therefore, data from these in vitro assays have to be carefully evaluated to allow sound extrapolation to the in vivo situation.