Current Drug Metabolism - Volume 12, Issue 1, 2011

Ochratoxin A (OTA) as a carcinogenic of group 2B to humans is produced by various fungi strains as Aspergillus and Penicillium. It is one of the most common contaminant in foodstuff. OTA is nephrotoxic, hepatotoxic, teratogenic, and immunotoxic and is assumed to cause Balkan Endemic Nephropathy (BEN), a chronic kidney disease in humans when it is digested in combination with mycotoxin citrinin. The metabolism affects greatly the fates and the toxicity of a mycotoxins in humans, animals, and plants. The understanding of the metabolism of mycotoxins by the organism as fungi, yeast, bacteria and enzymes would be very helpful for the control of the contamination by the mycotoxins in foods and feeds, and understanding of the biotransformation of the mycotoxin in the body of humans, animals, plants, microorganisms would be beneficial to the risk assessment of food safety. In animals and humans, OTA can be metabolized in the kidney, liver and intestines. Hydrolysis, hydroxylation, lactone-opening and conjugation are the major metabolic pathways. OTalpha (OTα) formed by the cleavage of the peptidic bond in OTA is a major metabolite not only in animals and humans, but also in microorganisms and enzyme systems. It is considered as a nontoxic product. However, the lactone-opened product (OP-OTA), found in rodents, is higher toxic than its parent, OTA. (4R)-4-OH-OTA is the major hydroxy product in rodents, whereas the 4S isomer is the major in pigs. 10-OH-OTA is currently found only in rabbits. Furthermore, OTA can lose the chlorine on C-5 to produce ochratoxin B (OTB), and OTB is further to 4-OH-OTB and ochratoxin β(OTβ). Ochratoxin quinine/hydroquinone (OTQ/OTHQ) is the metabolite of OTA in animals. In addition, the conjugates of OTA such as hexose and pentose conjugates can be found in animals. Such more polar metabolites make OTA to eliminate faster. Currently, a debate exits on the formation of OTA-DNA adducts. Plants can metabolize OTA as well. OH-OTA methyl ester and OH-OTA-β-glucoside are formed in many plants besides OTα and OH-OTA. OTA can be biotransformed into OTα by some yeast strains. Fungi can produce some of the same metabolites as animals. OTα, OTβ, 4-R-OH-OTA, 4-R-OHOTB, and 10-OH-OTA are the metabolites in fungi. Several commercial enzymes are able to biodegrade OTA into the nontoxic OTα efficiently. This review on the metabolism of OTA helps to well understand the fate of OTA in different organisms, as well as provides very crucial information for toxicology and food safety assessments on human health.

The RNA interference (RNAi) is a biological process by which a double stranded RNA (dsRNA also called small interfering RNA - siRNA) triggers the sequence-dependent degradation of a target RNA within the cellular environment. Thus siRNAs can be used to combat the expression of deleterious gene(s) causing disease or to destroy invading pathogen RNAs. Despite their enormous therapeutic potential, the use of siRNA as drugs presents two major problems: the difficulties to identify optimal delivery systems and the possible induction of different unwanted side effects. In this review, after presenting an overview about the mechanisms ruling the process of RNAi, we focus the attention on the description of the strategies developed to optimise systemic siRNA delivery; in this sense, considerations about the attempts to improve siRNA stability in the biological environment, the development of synthetic vectors for siRNA delivery, the siRNA bio-distribution and pharmacokinetics together with the selection of siRNA targeted delivery systems, are discussed. Since in the optimisation of the siRNA delivery systems the minimization of siRNA side effects should not be neglected, in the last part of the review we consider the problems related to the possible induction of siRNA mediated side effects focusing on the so called microRNA like off-targeting.

Bioavailability and effects of xenobiotics are dependent on absorption, metabolism and elimination of the respective compounds. Hepatocytes are critically important in drug modification and excretion. Molecules like organic anion transporters mediate hepatocyte uptake of xenobiotics which are subsequently modified by phase I enzymes with cytochrome (CYP) P450 isoenzymes like CYP3A4 being the most important. Phase II enzymes including glucuronosyltransferases further increase aqueous solubility of the respective compounds. The canalicular transport of these substances into the bile is mainly arranged by ATP-binding cassette transporters. Variations in the activity of these enzymes and transporters explain altered drug activity, elimination and eventually increased half-life and toxicity of xenobiotics. Body composition affects distribution of several drugs and fat mass may have to be taken into account in determining appropriate doses of lipophilic compounds. Adiposity is increasingly prevalent in western countries and about half of the adult population is overweight or even obese. Obesity is often associated with an enhanced storage of fat in hepatocytes and hepatic steatosis is diagnosed in nearly 30% of adults. Although this is a benign condition fatty liver is more susceptible to insults leading to non-alcoholic steatohepatitis (NASH) associated with inflammation and liver fibrosis. There is increasing evidence that drug metabolizing enzymes/ transporters are differentially expressed in hepatic steatosis and NASH. Data obtained from animals, patients and in-vitro models suggesting altered expression of transcription factors, transporters and enzymes involved in drug metabolism in non-alcoholic fatty liver disease are summarized in the current review.

Cytochrome P450-mediated bioactivation of drugs to reactive metabolites has been reported to be the first step in many adverse drug reactions. Metabolic activation of cyclic tertiary amines often generates a number of oxidative products including Ndealkylation, ring hydroxylation, α-carbonyl formation, N-oxygenation, and ring opening metabolites that can be formed through iminium ion intermediates. Therapeutic pharmaceuticals and their metabolites containing a cyclic tertiary amine structure have the potential to form iminium intermediates that are reactive toward nucleophilic macromolecules. Examples of cyclic tertiary amines that have the potential for forming reactive iminium intermediates include the piperazines, piperidines, 4-hydroxypiperidines, 4-fluoropiperidines and related compounds, pyrrolidines and N-alkyltetrahydroquinolines. Major themes explored in this review include bioactivation reactions for cyclic tertiary amines, which are responsible for the formation of iminium intermediates, together with some representative examples of drugs and guidance for discovery scientists in applying the information to minimize the bioactivation potential of cyclic amine-based compounds in drug discovery. Potential strategies to abrogate reactive iminium intermediate formation are also discussed.

Malaria and HIV/AIDS remain diseases of public health importance in sub-Saharan Africa as both infections are responsible for high morbidity and mortality rates. Malaria disproportionately affects young children and pregnant women and HIV/AIDS affects mostly adolescents and young adults. The widespread nature of both infections has led to co-infection in many residents of sub-Saharan African countries. HIV-infected individuals are more susceptible to frequent attacks of malaria thus requiring combination antiretroviral therapy and antimalarial drugs. There is, in general, lack of information on the influence of the chronic use of antiretroviral medicines on the outcome of repeated treatment of malaria. Pharmacokinetic drug interactions with HIV medications that lead to sub-therapeutic concentrations of antimalarial drugs will promote drug resistance in patients with malaria. The objective of this review is to summarize the available information on the adverse drug reactions and drug interactions of commonly used antimalarial drugs in the context of combination antiretroviral therapy and propose a clinical pharmacology research plan to develop dosing recommendations for patients with malaria and HIV co-infection.

Numerous drugs with different mechanisms of action and different pharmacologic profiles are being used with the aim of improving glycemic control in patients with type 2 diabetes. Therapeutic options for patients with type 2 diabetes and chronic kidney disease (CKD) are limited because a reduced glomerular filtration rate results in the accumulation of certain drugs and/or their metabolites. Conventional oral hypoglycemic agents, such as sulfonylurea (SU), are not suitable due to the risk of prolonged hypoglycemia; furthermore, metformin is contraindicated for moderate to advanced CKD. Therefore, in order to achieve good glycemic control, insulin injection therapy remains the mainstay of treatment in diabetic patients with moderate to advanced CKD, particularly in those receiving dialysis therapy. However, some agents have been used even in patients with CKD. Repaglinide and mitiglinide are rapid- and short-acting insulinotropic SU receptor ligands. They are rarely accompanied by hypoglycemia, and are attractive therapeutic options even in the dialysis population. In addition, alpha-glucosidase inhibitors are rarely accompanied by hypoglycemia and are administered without dose adjustments in dialysis patients. However, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines recommended that alpha-glucosidase inhibitors should be avoided in patients with advanced stage CKD and on dialysis. Furthermore, mitiglinide is not currently used in the US. Thus, recommended oral antidiabetic agents differ between countries. Moreover, dipeptidyl peptidase-4 inhibitors and incretin mimetics are new antihyperglycemic agents, which may be used more frequently in the future in patients with type 2 diabetes and CKD. Here, we describe the pharmacokinetics, metabolism, clinical efficacy, and safety of oral antidiabetic agents for patients with CKD, including those receiving dialysis.