Expert Opinion on Drug Metabolism & Toxicology

Dutheil, Fabien; Jacob, Aude; Dauchy, Sandrine; Beaune, Philippe; Scherrmann, Jean-Michel; Declèves, Xavier; Loriot, Marie-Anne

doi: 10.1517/17425255.2010.510832pmid: 20843279

Importance of the field: The identification of xenobiotic metabolizing enzymes (i.e., CYP) and transporters (i.e., ABC transporters) (XMET) in the human brain, including the BBB, raises the question whether these transporters and enzymes have specific functions in brain physiology, neuropharmacology and toxicology.Areas covered in this review: Relevant literature was identified using PubMed search articles published up to March 2010. Search terms included ‘ABC transporters and P450 or CYP’, ‘drug metabolism, effect and toxicity’ and ‘neurodegenerative disease (Alzheimer and Parkinson diseases)’ restricted to the field of ‘brain or human brain’.What the reader will gain: This review aims to provide a better understanding of XMET functions in the human brain and show their pharmacological importance for improving drug delivery and efficacy and also for managing their side effects. Finally, the impact of brain XMET activity during neurodegenerative processes is discussed, giving an opportunity to identify new markers of human brain diseases.Take home message: During the last 2 decades, much evidence concerning the specific distribution patterns of XMET, their induction by xenobiotics and endobiotics and their genetic variations have made cerebral ABC transporters and CYP enzymes key elements in the way individual patients respond to centrally acting drugs.

Duckett, Derek R; Cameron, Michael D

doi: 10.1517/17425255.2010.506873pmid: 20684746

Importance of the field: A concerted effort by the pharmaceutical industry over the last decade has led to the successful clinical development of protein kinase inhibitors as effective targeted therapies for certain cancers.Areas covered in this review: This review details eight small molecule kinase inhibitors that have been approved for the treatment of cancer in either the US or Europe as of March 2010: imatinib, sorafenib, gefitinib, erlotinib, dasatinib, lapatinib, sunitinib and nilotinib. These eight compounds vary from the relatively specific inhibitor lapatinib to the more promiscuous kinase inhibitors dasatinib and sunitinib.What the reader will gain: A brief discussion on the biology of each inhibitor, selectivity over other kinases and toxicity is provided. A more detailed discussion on the metabolism, drug transporters, drug–drug interactions and possible roles of metabolism in compound toxicity is provided for each compound.Take home message: The majority of the currently approved kinase inhibitors is heavily influenced by drug transporters and significantly affected by CYP3A4 inhibitors/inducers. At least three, gefitinib, erlotinib and dasatinib, are metabolized to form reactive metabolites capable of covalently-binding biomolecules.

He, Shu-Ming; Yang, An-Kui; Li, Xiao-Tian; Du, Yao-Min; Zhou, Shu-Feng

doi: 10.1517/17425255.2010.510132pmid: 20701553

Importance of the field: Cancer patients on chemotherapy treatment often seek herbal therapies and this may alter the clearance of anticancer drugs.Areas covered in this review: Many anticancer drugs are metabolized by CYPs and are substrates of P-glycoprotein, breast cancer resistance protein and multi-drug resistance proteins. CYPs and drug transporters are subject to inhibition and/or induction by the herbal medicines used by cancer patients and the metabolism and pharmacokinetics of anticancer agents may be altered by herbal products. There are increased reports on the interaction of herbal medicines with anticancer agents. A clinical study in cancer patients reported that treatment of St John's wort at 900 mg/day orally for 18 days decreased the plasma levels of the active metabolite of irinotecan, SN-38, by 42%. In healthy subjects, treatment with St John's wort for 2 weeks significantly decreased the systemic exposure of imatinib by 32%. Induction and/or inhibition of CYPs and transporters is considered an important mechanism for these interactions.What the reader will gain: Potential interactions of herbal medicines with anticancer agents have become a safety concern in cancer chemotherapy.Take home message: Further studies are warranted to investigate the efficacy and safety profiles of herbal medicines commonly used by cancer patients.

Palatini, Pietro; Orlando, Rocco; De Martin, Sara

doi: 10.1517/17425255.2010.503704pmid: 20604736

Importance of the field: Inhibition of CYP-mediated metabolism is the most frequent and dangerous drug interaction, which causes serious problems in drug development, drug approval and clinical practice. The wide interindividual variability in the magnitude of such interactions constitutes the main hurdle to their management by dose adjustment.Area covered in this review: This review focuses on a recently identified source of variability in the extent of inhibitory drug interactions, namely liver functional status. It examines the differential effect of liver dysfunction on reversible and mechanism-based CYP inhibition, as well as on inhibition accompanied by plasma protein-binding displacement.What the reader will gain: Liver disease progression is accompanied by a proportional, drastic reduction in the magnitude of reversible inhibitory drug interactions due to decreased hepatic uptake of the inhibitor and reduced CYP expression. The degree of mechanism-based inhibition is reduced to a much lesser extent as it is only influenced by the decreased hepatic content of the inhibited CYP enzyme. Metabolic inhibition accompanied by plasma protein-binding displacement results in a disproportionate rise in free drug concentration, the extent of which increases as liver function worsens.Take home message: For an appropriate management of inhibitory drug interactions, the patient's liver functional status and the mechanism of inhibition must be taken into consideration.

Sangar, Michelle C; Bansal, Seema; Avadhani, Narayan G

doi: 10.1517/17425255.2010.503955pmid: 20629582

Importance of the field: Microsomal CYPs are critical for drug metabolism and toxicity. Recent studies show that these CYPs are also present in the mitochondrial compartment of human and rodent tissues. Mitochondrial CYP1A1 and 2E1 show both overlapping and distinct metabolic activities compared to microsomal forms. Mitochondrial CYP2E1 also induces oxidative stress. The mechanisms of mitochondria targeting of CYPs and their role in drug metabolism and toxicity are important factors to consider while determining the drug dose and in drug development.Areas covered in this review: This review highlights the mechanisms of bimodal targeting of CYP1A1, 2B1, 2E1 and 2D6 to mitochondria and microsomes. The review also discusses differences in structure and function of mitochondrial CYPs.What the readers will gain: A comprehensive review of the literature on drug metabolism in the mitochondrial compartment and their potential for inducing mitochondrial dysfunction.Take home message: Studies on the biochemistry, pharmacology and pharmacogenetic analysis of CYPs are mostly focused on the molecular forms associated with the microsomal membrane. However, the mitochondrial CYPs in some individuals can represent a substantial part of the tissue pool and contribute in a significant way to drug metabolism, clearance and toxicity.

Garcia-Serna, Ricard; Mestres, Jordi

doi: 10.1517/17425255.2010.509343pmid: 20662552

Importance of the field: Anticipating the likely side effect profile of drugs is an aspect of key importance in current drug discovery, development and marketing. It was recently shown that drug pairs having similar side effect profiles had also affinity for a common target. Acknowledging that most drugs have a rich polypharmacology, we provide proof that drugs related by side effect similarity have in fact affinities for multiple common targets beyond their primary targets and set the basis for the use of comparative pharmacology to anticipate drug side effects.Areas covered in this review: Nomenclature issues to be able to identify and properly store drugs, targets and side effects from multiple public sources; the construction of drug networks from side effect similarity and the inference of common targets among them; polypharmacology and data completeness; methods for in silico target profiling; and comparative pharmacology and inference of common side effects.What the reader will gain: The reader is provided with a detailed step-by-step analysis of the entire process from predicting the target profile of a compound to anticipating its side effect profile, and a discussion on the particular needs and limitations found at each stage of the process through illustrative examples.Take home message: Comparing preclinical pharmacology data obtained in vitro but also predicted in silico using modern virtual screening methods represents an attractive strategy to anticipate clinical drug side effects.

Scheen, André J

doi: 10.1517/17425255.2010.513699pmid: 20707611

Importance of the field: Type 2 diabetes is an increasingly prevalent disease resulting from various complex combinations of defects in insulin secretion and insulin action. Adequate blood glucose control is necessary to minimize complications. DPP IV inhibitors (sitagliptin, vildagliptin, saxagliptin) offer new options for combined pharmacological therapy.Areas covered in this review: An extensive literature search was performed to analyze the potential pharmacokinetic (PK) and pharmacodynamic (PD) interactions between metformin (first-line drug for the management of type 2 diabetes) and sitagliptin (first commercialized DPP IV inhibitor). Metformin and sitagliptin may be administered together, either separately or in fixed-dose combination.What the reader will gain: Updated information about PK/PD data on metformin alone, sitagliptin alone and sitagliptin plus metformin. Metformin and sitagliptin are not prone to PK drug–drug interactions. Their co-administration, either separately or in a fixed-dose combination, improves blood glucose control more potently than either compound separately, without hypoglycemia and without increasing metformin-related gastrointestinal side effects.Take home message: The combination sitagliptin plus metformin may be used as a first- or second-line therapy in the management of type 2 diabetes.

Colon-Gonzalez, Francheska; Kraft, Walter K

doi: 10.1517/17425255.2010.513970pmid: 20795794

Importance of the field: Chemotherapy induced nausea and vomiting (CINV) is a common complication in the treatment of patients with cancer. The introduction of the first in class neurokinin-1 receptor antagonist aprepitant provided additive control on CINV in combination to existing antiemetics. Due to formulation issues, aprepitant is only available for oral administration. Fosaprepitant, a prodrug of aprepitant, was introduced to the market in 2008 as an intravenous bioequivalent to aprepitant.Areas covered in this review: This review examines the chemical development of fosaprepitant, its pharmacokinetic properties, approved uses and potential applications.What the reader will gain: The reader will get up-to-date information on the pharmacology and clinical uses of fosaprepitant. Clinical studies have demonstrated pharmacokinetic bioequivalence of aprepitant 125 mg to fosaprepitant 115 mg, as well as comparable efficacy in prevention of acute and delayed emesis following the first day of chemotherapy regimens.Take home message: Fosaprepitant is an intravenous prodrug of aprepitant that offers a new alternative to patients with CINV. Currently, fosaprepitant can substitute oral aprepitant in day 1 of a 3-day regimen. Current studies show that a single-day fosaprepitant regimen is also bioequivalent to the 3-day aprepitant regimen; this could significantly simplify the care for CINV patients in the future.

Kuti, Effie L; Kuti, Joseph L

doi: 10.1517/17425255.2010.518143pmid: 20822479

Importance of the field: Anidulafungin is one of three available intravenous echinocandins that plays an important role in the treatment of serious fungal infections. Currently, anidulafungin is approved for the treatment of esophageal candidiasis, candidemia and other invasive Candida infections including intra-abdominal abscesses and peritonitis.Areas covered in this review: This paper covers a comprehensive review of anidulafungin.What the reader will gain: The reader will be provided the most recent data available regarding the pharmacology, pharmacokinetics, in vitro activity and clinical utility of anidulafungin for the treatment of serious fungal infections.Take home message: Echinocandin antifungals, such as anidulafungin, are now considered first line for the treatment of candidemia and invasive candidiasis, particularly in critically ill patients or those who have previously received azole therapy. Anidulafungin has potent in vitro activity against Candida and Aspergillus species, predictable pharmacokinetics that does not require dosage adjustment, few drug interactions and is well tolerated. Because of these favorable characteristics, anidulafungin is an important addition to our antifungal armamentarium.

Hu, Miao; Tomlinson, Brian

doi: 10.1517/17425255.2010.513700pmid: 20716034

Importance of the field: Acromegaly is a rare and potentially life-threatening disease in adults related to excessive production of growth hormone (GH) by pituitary gland tumors and characterized by progressive somatic disfigurement that is associated with systemic manifestations related to organ overgrowth. Somatostatin analogs (SSAs) are effective in controlling GH/IGF-1 hypersecretion and in reducing tumor size.Areas covered in this review: We review and compare the pharmacokinetic and clinical efficacy of lanreotide, the second SSA available in the market, in its different formulations.What the reader will gain: This article concisely reviews the rationale of SSA treatment in acromegaly and the pharmacology and clinical efficacy of lanreotide and provides a detailed overview of its pharmacokinetic profiles in its slow release (SR) and autogel (ATG) formulations.Take home message: Lanreotide is an effective and well-tolerated drug for the treatment of acromegaly. Lanreotide ATG has a more favorable pharmacokinetic profile than lanreotide SR, which permits administration once every 28 – 56 days given deep subcutaneously and by self-injection rather than intramuscular injection every 7 – 14 days. In well-designed clinical trials, subcutaneous lanreotide ATG was shown to be no less effective than intramuscular lanreotide SR or octreotide treatment.