Fenofibrate: metabolic and pleiotropic effects

Disturbances of lipoprotein metabolism represent one of the most important risk factors for vascular events. However, dyslipidaemic patients often have a number of additional abnormalities (such as endothelial dysfunction, hypertension, low-grade inflammation, haemostatic abnormalities and hyperuricaemia) that may accelerate the atherosclerotic process. Thus, the ideal lipid-modifying drug, along with exerting beneficial effects on lipoprotein metabolism, should also improve these coexisting disturbances. Fibric acid derivatives (fibrates) are a class of lipid-modifying drugs mainly used in patients with elevated triglyceride levels. These drugs mainly exert their actions via the activation of specific nuclear receptors called peroxisome proliferator-activated receptors alpha (PPARalpha). In this review, we summarize the current evidence suggesting that fenofibrate, one of the most widely used fibric acid derivatives, along with its well established actions on lipids also exerts several other antiatherogenic actions. Based on recently published studies, fenofibrate is a useful option for patients with primary combined dyslipidaemias or secondary dyslipidaemias, such as those associated with diabetes mellitus, metabolic syndrome or HIV infection. Additionally, in cases of refractory dyslipidaemia, the combination of fenofibrate with statins is a therapeutic option.     

Nimodipine: synthesis and metabolic pathway

Key step of the synthesis of the calcium antagonistic cerebral vasodilator (+/-) isopropyl-2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (Bay e 9736, nimodipine) (5) is the cyclizing Michael addition of 3 onto 4. A pharmacokinetic study with 14C-nimodipine in the rat revealed as major metabolites the dihydropyridines 6 and 8 as well as the pyridines 7, 9, 10, 11, 13 and 14. A potential metabolic pathway is discussed involving ether cleavage and oxidation to the pyridine form as primary biotransformation steps. Reference metabolites were synthesized using 1,4-dihydropyridines with appropriate functionalities as precursors.     

Isoniazid: metabolic aspects and toxicological correlates

For over half a century, pyridine-4-carboxy hydrazide (isonicotinyl hydrazide; isoniazid - INH) has been a front-line weapon in the battle against tuberculosis. Its metabolism has been the subject of important research, much of which has focused on the pharmacodynamic and toxicological aspects of certain INH metabolites. Since 1952, when the drug was first introduced, multiple INH metabolites have been identified, including hydrazine (HZ), isonicotinic acid (INA), ammonia, the acetylated derivative N(1)-acetyl-N(2)-isonicotinylhydrazide (AcINH), hydrazones with pyruvic and ketoglutaric acids (INH-PA and INH-KA, respectively), monoacetylhydrazine (AcHZ), diacetylhydrazine (DiAcHZ), and oxidizing free radicals. Their formation is the result of hydrolysis (INA, HZ), cytochrome P450 (CYP)-dependent oxidation (HZ, NH(3), oxidizing free radicals), and N-acetyltransferase (NAT) activity (AcINH, AcHZ, DiAcHZ). Doubts remain about isonicotinamide (INAAM) as an INH metabolite in mammals. Quantitatively speaking, one of the major metabolites is AcINH, which is produced by the enzyme NAT. It has virtually no antitubercular activity and is far less toxic than INH. Its formation and elimination are genetically controlled, and its elimination profile is trimodal (rapid, intermediate, and slow acetylation). Slow acetylation, which is transmitted as an autosomal recessive trait, increases the risk for peripheral neurotoxicity and hepatotoxicity in INH users. Thus far, there is no conclusive pharmacogenetic evidence that the formation of HZ and oxidizing radicals are linked to CYP polymorphisms. This article examines INH, HZ and its mono- and diacetylated metabolites, and ammonia (which in vitro and in vivo studies indicate as another derivative of HZ) in terms of their potential to cause neurotoxic and hepatotoxic effects (the two major forms of INH toxicity observed in animals and humans). INH hepatotoxicity seems to be related mainly to HZ, AcHZ, and other HZ metabolites that are capable of generating free radicals. The pathological aspects of slow INH acetylation will be discussed in relation to the drug's hepato- and neurotoxic effects. The mechanism underlying INH neurotoxicity has yet to be fully defined. The metabolite(s) involved in this phenomenon remain obscure although a major role is clearly played by HZ (and possibly also by the ammonia it releases). There is some evidence of the involvement of gamma-glutamyl HZ and of a chemical analogue of a Schiff base formed by INH and pyridoxal-phosphate. Recent findings have also revealed important interactions between INH and the various isoforms of CYP, and these may play a role in clinically relevant interactions between INH and several other drugs. All of these aspects of INH will be covered in the review.     

METAPRINT: a metabolic fingerprint

METAPRINT, a metabolic fingerprint based on predicted metabolic pathways and corresponding potential metabolites, has been developed. Calculated drug-likeness parameters (logP and MW) have been added into METAPRINT to achieve metabolic discrimination among the members of a chemical library. The application of METAPRINT in the design of cassette dosing experiments is demonstrated on a library of alpha-1a antagonists. Cassette design was performed by maximizing the intracassette Euclidean distances between compounds in METAPRINT space, using Metropolis Monte Carlo simulated annealing. Calculated distances in METAPRINT space were in accordance with experimental data.     

Discontinued drugs in 2005: endocrine and metabolic

This perspective describes the compounds from the endocrine and metabolic area that were discontinued during the calendar year 2005. This is a continuation of a series of perspectives of each of the editorial areas summarized by Expert Opinion on Investigational Drugs. The candidates for this summary were being developed in the areas of treatment of diabetes and diabetes complications, as well as reproductive and urogenital heath issues.     

Discontinued drugs in 2008: endocrine and metabolic

This perspective summarizes key compounds from the endocrine and metabolic area that were discontinued during the calendar year 2008. This is a continuation in a series of perspectives of each of the editorial areas summarized by Expert Opinion on Investigational Drugs. The candidates covered in this summary were being developed for the treatment of diabetes, diabetic complications, anti-atherosclerosis and obesity.     

Discontinued drugs in 2005: endocrine and metabolic

This perspective describes the compounds from the endocrine and metabolic area that were discontinued during the calendar year 2005. This is a continuation of a series of perspectives of each of the editorial areas summarized by Expert Opinion on Investigational Drugs. The candidates for this summary were being developed in the areas of treatment of diabetes and diabetes complications, as well as reproductive and urogenital health issues.     

Trimethylamine: metabolic, pharmacokinetic and safety aspects

Trimethylamine (TMA) is a volatile tertiary aliphatic amine that is derived from the diet either directly from the consumption of foods containing TMA, or by the intake of food containing precursors to TMA such as trimethylamine-N-oxide (TMNO), choline and L-carnitine. Following oral absorption in humans, TMA undergoes efficient N-oxidation to TMNO, a reaction catalyzed by the flavin-containing monooxygenase (FMO) isoform 3 enzyme. TMNO subsequently undergoes excretion in the urine, although, evidence also suggests that metabolic retro-reduction of TMNO can occur. Whilst the pharmacokinetics of TMA and TMNO has not been fully elucidated in humans, a number of studies provide information on the likely fate of dietary derived TMA. Trimethylaminuria is a condition that is characterized by a deficiency in FMO3 enzyme activity, resulting in the excretion of increased amounts of TMA in bodily fluids such as urine and sweat, and breath. A human FMO3 database has been established and currently twenty-eight variants of the FMO3 gene have been reported including twenty-four missense, three nonsense, and one gross deletion mutation. Whilst TMA and TMNO are generally regarded as non-toxic substances, they are of clinical interest because of their potential to form the carcinogen N-nitrosodimethylamine.     

药物性肝损伤的代谢、遗传学机制

药物引起的肝损伤是引起急性肝功能衰竭的重要原因,也是导致治疗药物退市的主要原因。药物性肝损伤的发病机制复杂,其中以代谢、遗传学机制为主。该文综述了成人常用药物引起肝损伤的机制,并就热点问题进行讨论。旨在探讨这些研究可能的临床意义,为进一步阐明药物性肝损伤的发病机制指明方向。     

Oximes: metabolic activation and structure-allergenic activity relationships

Metabolic activation of chemicals (prohaptens) in the skin can cause allergic contact dermatitis. We have explored structure-allergenic activity relationships for seven potential oxime prohaptens using the local lymph node assay and a GSH trapping screen with liver microsomes. The general structure-allergenic activity relationships found were that an alpha,beta-unsaturation is necessary for an oxime to be a prohapten and that increased steric hindrance around this double bond leads to reduction in sensitizing capacity. We also found that sensitizing oximes can be distinguished in vitro from nonsensitizers by monitoring of mono-oxidized (+16 Da) GSH conjugates in the GSH trapping screen. However, care should be taken when interpreting data from GSH trapping screens, as nonsensitizers may also form GSH conjugates via alternative mechanisms. This investigation emphasizes the importance of considering cutaneous bioactivation in toxicity assessment of chemicals used in contact with the skin.     

Fluvoxamine: metabolic fate in animals

The metabolic fate in animals of the antidepressant compound fluvoxamine was investigated. The 14C-labeled drug was administered orally to dogs, rats, hamsters, and mice, and excretion in urine and feces was measured. Chromatographic patterns of the urines were developed by high performance liquid chromatography. These patterns were used as guides in the isolation of the metabolites, its initial step consisting of concentration of the radioactivity in the urine pools in a conical precolumn, followed by separation in the same HPLC system as used for the metabolite patterns. Altogether, 32 radioactive substances were isolated from the urine pools of the four animal species. They were all identified by the combined use of proton nuclear magnetic resonance and mass spectrometry, and by information obtained from chromatographic behavior and color reactions. Several of the 32 compounds were identical, leaving a total of 11 different metabolites in the four species. In all the animal species, the main focus of fluvoxamine degradation was its aliphatic methoxyl group. In three species, this resulted in the corresponding carboxylic acid as the main metabolite, but in the mouse the corresponding alcohol, in glucuronidated form, was at least as important. In mouse and hamster, the methyl ester was a minor metabolite. Products of acetylation or oxidative removal of the primary amino group accounted for only minor proportions of the metabolite patterns. While fluvoxamine itself has the (E)-configuration, several metabolites occurred both in the (E)- and the (Z)-form. The parent compound was isolated only from the urine of dogs, it accounted for less than 10% of the urinary radioactivity.