Current Drug Metabolism (v.15, #7)

This article reviews in vitro metabolic and in vivo pharmacokinetic drug-drug interactions of nine antifungal agents: six azoles (fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, and voriconazole) and three echinocandins (anidulafungin, caspofungin, and micafungin). In in vitro interaction studies, itraconazole, ketoconazole, and miconazole were found to have higher inhibitory effects on cytochrome P450 (P450 or CYP) 3A4 and 3A5 activities than the other azoles or echinocandins did. Fluconazole, itraconazole, and voriconazole were relatively less potent inhibitors of CYP3A5 than of CYP3A4. The inhibitory effects of fluconazole, itraconazole, ketoconazole, and voriconazole against CYP3A4 and CYP3A5 seemed to be correlated with their dissociation constants for CYP51 (lanosterol 14α-demethylase) from Candida albicans. In in vivo pharmacokinetic studies, itraconazole was found to be a potent clinically important inhibitor of CYP3A4/5 substrates, and fluconazole and voriconazole increased the blood/plasma concentrations of not only CYP3A4/5 substrates but also CYP2C9 substrates. Miconazole was a potent inhibitor of all P450s investigated in vitro, although there are few detailed studies on the clinical significance of this except for CYP2C9. For the echinocandins, no marked inhibition of P450 activities, except for some inhibition of CYP3A4/5 activity, was observed in vitro. The blood/plasma concentrations of concomitant drugs were not markedly affected by coadministration of echinocandins in vivo, suggesting that echinocandins do not cause clinically significant interactions with drugs that are metabolized by P450s via the inhibition of metabolism. The differential effects of these antifungal agents on P450 activities must be considered when clinicians select antifungal agents for patients also receiving other drugs.

Role of Membrane Transporters and Metabolizing Enzymes in Ocular Drug Delivery by Ramya Krishna Vadlapatla, Aswani Dutt Vadlapudi, Dhananjay Pal, Ashim K. Mitra (680-693).
Ocular disorders can significantly lower a patient's quality of life. Centers for Disease Control and Prevention's Vision Health Initiative have estimated that the number of people affected by age-related ocular diseases may be doubled in the United States by 2030. Although availability of newer therapeutics has improved the prognosis of ocular diseases, poor ocular bioavailability still remains a major concern. Combinations of pharmacodynamic and pharmacokinetic barriers have been known to determine the amount of drug delivered to the target tissue. However, presence of membrane transporters and metabolizing enzymes pose a significant challenge to ocular drug disposition. Scientific literature confirms the expression of efflux/ATP-binding cassette transporters, influx/solute carrier transporters and several metabolic enzymes including oxidoreductases, hydrolases and transferases in different ocular tissues. Therefore, this review article describes the anatomical features of the eye and various barriers regulating ocular drug disposition. Differential expression of membrane transporters and metabolizing enzymes in normal and diseased states are briefly discussed. Further, the significance of transporter- metabolism interplay in ophthalmic drug design and various ocular drug delivery strategies are also outlined.

Safety and Tolerability of Agomelatine: Focus on Hepatotoxicity by Maximilian Gahr, Wolfgang Kratzer, Michael Fuchs, Bernhard J. Connemann (694-702).
Hepatotoxicity related to antidepressive pharmacotherapy is a major safety concern, particularly considering that severe forms of hepatic failure with fatal outcome have been reported. Severe hepatotoxic adverse drug reactions were also reported for agomelatine (AGM), an antidepressive agent, which was approved for the treatment of major depressive disorder (MDD) in adults by the European Medicines Agency (EMA) in February 2009. Its general safety and tolerability profile appears to be favourable or similar in comparison to other antidepressants, particularly regarding metabolic aspects, sexual functioning, gastrointestinal side effects, and discontinuation phenomena. Epidemiology and pathophysiology of AGM-related hepatotoxicity are currently poorly understood. Pooled data from clinical trials indicate that patients treated with AGM demonstrate increased prevalence rates of elevated liver transaminases (> 3 x ULN; 1.34% on AGM 25 mg/day, 2.51% on AGM 50 mg/day) in comparison to placebo (0.5%). AGM-related hepatotoxic adverse drug reactions are unpredictable and usually occur as asymptomatic increases of liver enzymes, which develop during the first months of treatment and mostly recover after discontinuation of AGM-treatment or even on continued treatment. Liver injury due to AGM-related hepatotoxicity is mostly hepatocellular. The underlying mechanism appears to be idiosyncratic. Cholestatic or hypersensitivity reactions have not yet been reported. Some evidence suggests dose-dependence of AGM-related hepatotoxicity. In a recent post-authorisation opinion of the EMA, hepatotoxic reactions related to AGM were declared as an important identified risk and new contraindications for treatment with AGM were released (hypersensitivity to AGM, elevations of liver enzymes > 3 x ULN, hepatic impairment (not further specified), parallel use of potent CYP1A2 inhibitors). Considering these aspects, treatment with AGM must only be performed under strict accordance with the recently modified prescribing information. A final evaluation of AGM-related hepatotoxicity is currently not possible; further studies are necessary.

Resveratrol-Mediated Reversal of Tumor Multi-Drug Resistance by Yutong Hu, Chuangang Li, Hong Li, Molin Li, Xiaohong Shu (703-710).
Multi-drug resistance (MDR) to cancer chemotherapy is a major obstacle to the effective treatment of tumors. Resveratrol, a natural product, may inhibit efflux transporters, such as P-glycoprotein (P-gp), multi-drug resistance-associated protein (MRP) and breast cancer resistance protein (BCRP), and could become a potential multi-drug-resistant regulator. But it remains unclear how resveratrol exerts its reversal effect. In this review, we attempt to reveal the interactions between resveratrol and ABC transporter proteins, and summarize the research profile of resveratrol's reversal mechanisms, thus to provide pivotal information on the development and application of multi-drug resistance reversal agents.

Pharmacogenetic Prediction of Individual Variability in Drug Response Based on CYP2D6, CYP2C9 and CYP2C19 Genetic Polymorphisms by Shafqat Rasul Chaudhry, Sajjad Muhammad, Moritz Eidens, Marco Klemm, Dilaware Khan, Thomas Efferth, Maria-Paz Weisshaar (711-718).
Interindividual variability in drug response depends on a number of genetic and environmental factors. The metabolic enzymes are well known for their contribution to this variability due to drug-drug interactions and genetic polymorphisms. The phase I drug metabolism is highly dependent upon the cytochrome P450 mono-oxygenases (CYP) and their genetic polymorphism leads to the variable internal drug exposures. The highly polymorphic CYP2C9, CYP2C19 and CYP2D6 isozymes are responsible for metabolizing a large portion of routinely prescribed drugs and contribute significantly to adverse drug reactions and therapeutic failures. In this review, two attractive and easily implementable approaches are highlighted to recommend drug doses ensuring similar internal exposures in the face of these polymorphisms. The first approach relies on subpopulation-based dose recommendations that consider the original population dose as an average of the doses recommended in genetically polymorphic subpopulations. By using bioequivalence principles and assuming linear gene-dose effect, dose recommendations can be made for different metabolic phenotypes. The second approach relates area under the curve to two characteristic parameters; the contribution ratio (CR), computes for the contribution of the metabolic enzyme and the fractional activity (FA), considers the impact of the genetic polymorphism. This approach provides valid and error free internal drug exposure predictions and can take into consideration genetic polymorphisms and drug interactions and/ or both simultaneously. Despite certain advantages and limitations, both approaches provide a good initial frame-work for devising models to predict internal exposure and individualize drug therapy, one of the promises from human genome project.

Background: Cytochrome monooxygenases P450 enzymes (CYPs) are terminal oxidases, belonging to the multi-gene family of heme-thiolate enzymes and located in multiple sites of ER, cytosol and mitochondria. CYPs act as catalysts in drugs metabolism. ; Areas covered: This review highlights the mitochondrial and microsomal CYPs metabolic functions, CYPs mediated ROS generation and its feedback, bioactivation of drugs and related hypersensitivity, metabolic disposition as well as the therapeutic approaches. ; What the readers will gain: CYPs mediated drugs bioactivation may trigger oxidative stress and cause pathophysiology. Almost all drugs show some adverse reactions at high doses or accidental overdoses. Drugs lead to hypersensitivity reactions while metabolic predisposition to drug hypersensitivity exaggerates it. Mostly different intermediate bioactive products of CYPs mediated drug metabolism is the principal issue in this respect. On the other hand, CYPs are the main source of ROS. Their generation and feedback are of major concern of this review. Besides drug metabolism, CYPs also contribute significantly to carcinogen metabolism. Ultimately other enzymes in drug metabolism and antioxidant therapy are indispensible. ; Importance of this field: In a global sense, understanding of exact mechanism can facilitate pharmaceutical industries' challenge of developing drugs without toxicity. ; Ultimate message: This review would accentuate the recent advances in molecular mechanism of CYPs mediated drug metabolism and complex cross-talks between various restorative novel strategies evolved by CYPs to sustain the redox balance and limit the source of oxidative stress.

Protein Engineering: A New Frontier for Biological Therapeutics by Peter H. Tobin, David H. Richards, Randolph A. Callender, Corey J. Wilson (743-756).
Protein engineering holds the potential to transform the metabolic drug landscape through the development of smart, stimulusresponsive drug systems. Protein therapeutics are a rapidly expanding segment of Food and Drug Administration approved drugs that will improve clinical outcomes over the long run. Engineering of protein therapeutics is still in its infancy, but recent general advances in protein engineering capabilities are being leveraged to yield improved control over both pharmacokinetics and pharmacodynamics. Stimulus- responsive protein therapeutics are drugs which have been designed to be metabolized under targeted conditions. Protein engineering is being utilized to develop tailored smart therapeutics with biochemical logic. This review focuses on applications of targeted drug neutralization, stimulus-responsive engineered protein prodrugs, and emerging multicomponent smart drug systems (e.g., antibody-drug conjugates, responsive engineered zymogens, prospective biochemical logic smart drug systems, drug buffers, and network medicine applications).

Erratum: (757-758).