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PubMed1999

[Modern therapeutic possibilities in Parkinson disease].

Several new methods for the treatment of patients suffering from Parkinson's disease have been introduced during the last few years. COMT inhibitors are available in addition to levodopa with a decarboxylase inhibitor. COMT inhibitors enhance and prolong the effect of single levodopa doses. Severe side effects have been mentioned in connection with the COMT inhibitor tolcapone in recent months. Several new dopaminergic agonists now provide efficacious monotherapy in the early stages of the disease. This brings about a reduction in late problems of treatment such as dyskinesias and fluctuations. Stereotaxic operations in the pallidum and the subthalamic afford relief for these late complications of treatment in selected patients.

Antiparkinson Agents↗
PubMedDate not supplied

[Recent advances in Parkinson disease].

OBJECTIVE: To evaluate the latest advances in the diagnosis and symptomatic pharmacological treatment of patients with Parkinson's disease at different stages. DEVELOPMENT: In this article we summarize the criteria for clinical diagnosis of Parkinson's disease based on recent clinico-pathological studies. We evaluate the different therapeutic options at early and late stages of the illness in view of the results of recent, controlled, double-blind studies in which the efficacy of new dopaminergic agonists (carbergolin, pramipexol and ropinirol) and catechol-O-methyl-transferase enzyme inhibitors (COMT; entacapone and tolcapone) are compared with placebo and with established treatments (e.g. levodopa and bromocryptin). CONCLUSIONS: Levodopa is still the most important advance yet made in the treatment of Parkinson's disease, but new dopaminergic agonists and COMT inhibitors are useful additions to the possibilities available for the treatment of early and late stages of the illness and may be included in modern guidelines for treatment.

Antiparkinson Agents↗
PubMed2000

Issues important for rational COMT inhibition.

Levodopa is the most efficacious drug in the symptomatic treatment of Parkinson's disease. However, exogenously administered levodopa is extensively metabolized in the periphery by aromatic amino acid decarboxylase (AAAD) and catechol-O-methyltransferase (COMT) so that only 1% of an administered dose gains access to the brain. Even when levodopa is co-administered with an inhibitor of AAAD such as benserazide or carbidopa, the bulk (90%) of levodopa is converted by COMT to the therapeutically inactive 3-O-methyldopa. Two COMT inhibitors, tolcapone and entacapone, have recently been introduced as adjuncts to levodopa to further inhibit peripheral levodopa metabolism and thereby enhance brain levodopa availability. This paper reviews the pharmacokinetics, dosing schedule, peripheral and central effects, and safety profile of these agents.

Benzophenones↗
PubMed2000

The place of COMT inhibitors in the armamentarium of drugs for the treatment of Parkinson's disease.

Catechol-O-methyl transferase (COMT) inhibitors block the peripheral metabolism of levodopa, increase its plasma half-life, and enhance its brain availability. Two COMT inhibitors, tolcapone and entacapone, have recently been made available as adjunctive agents to levodopa. In PD patients with motor fluctuations, they have been shown to increase "on" time and reduce "off" time. In patients with more advanced disease, they provide similar benefits, but patients tend to experience less overall benefit and a greater likelihood of developing dopaminergic adverse events. Accordingly, closer monitoring is required. In stable patients who have not yet developed motor complications, there are preliminary data suggesting that they experience improvements in motor function and in activities of daily living. Finally, there are theoretical reasons to consider administering a COMT inhibitor to patients from the onset of levodopa therapy in order to reduce the likelihood that motor complications will develop. COMT inhibitors are easy to administer, do not require titration, and are generally well tolerated particularly in patients with relatively mild disease. Adverse events are primarily dopaminergic and can usually be controlled by levodopa dose adjustments. COMT inhibitors have thus proven to be a useful addition to the therapeutic armamentarium of PD.

Benzophenones↗
PubMed1997

Graphical analysis of 6-fluoro-L-dopa trapping: effect of inhibition of catechol-O-methyltransferase.

UNLABELLED: Graphical methods to analyze tracer time-course data allow reliable quantitation of the rate of incorporation of tracer from plasma into a "trapped" kinetic component, even when the details of the kinetic model are unknown. Applications of the method over long time periods often expose the slow reversibility of the trapping process. In the extended graphical method, both trapping rate and a presumed first-order loss rate constant are estimated simultaneously from the time-course data. METHODS: We applied the extended graphical method to 6-fluoro-L-dopa (6-FD), simultaneously estimating the rate of uptake (Ki) and the rate constant for loss from the trapped component (K(loss)) in a single fitting procedure. We applied this approach to study the effects of two catechol-O-methyl-transferase inhibitors on the kinetics of 6-FD in cynomolgus monkeys. RESULTS: Inhibition of peripheral O-methylation with either inhibitor, confirmed by high-performance liquid chromatography analysis of labeled compounds in arterial plasma, had no significant effect on Ki, in agreement with previously reported studies. In contrast, tolcapone, a catechol-O-methyl-transferase inhibitor, having central effects in addition to peripheral effects at the dosage used, decreased K(loss) by 40% from control values (p < 0.002), whereas nitecapone, which has no known central activity, had no significant effect. CONCLUSION: This method provides insight into the neurochemical basis for the kinetic behavior of 6-FD in both health and disease and may be used to define the action of centrally active drugs that influence the metabolism of dopamine.

Animals↗
PubMed1997

New options for treatment of Parkinson's disease.

New medications recently developed for treating Parkinson's disease include two inhibitors of catechol-O-methyltransferase (COMT), entacapone and tolcapone, which, by decreasing the elimination of levodopa, extend the duration of its effects. Increased 'on' time and less 'wearing-off' symptomatology can be expected with the use of these COMT inhibitors. Two non-ergot dopaminergic agonists (pramipexole and ropinirole) and a long-acting ergoline (cabergoline) are also being introduced. These dopaminergic agonists, like the ergot derivatives currently available (bromocriptine, lisuride, and pergolide), are useful as adjuncts to levodopa, and are also efficacious as monotherapies.

Antiparkinson Agents↗
PubMedDate not supplied

Tissue histopathology, clinical chemistry and behaviour of adult Comt-gene-disrupted mice.

Catechol-O-methyltransferase (COMT) enzyme is a widely distributed enzyme that catalyses O-methylation of catecholamines and other compounds having a catechol structure. Because there has been some concern about the consequences of a low COMT activity in the development of oestrogen-dependent cancers and because one of the COMT inhibitors, tolcapone, has caused serious liver injuries in Parkinsonian patients, the histopathology and clinical chemistry of Comt-gene-disrupted mice were studied at the age of 12 months. Owing to the high COMT activities in liver and kidney and the role of COMT in the metabolism of catechol oestrogens, special emphasis was given to the histology of the liver, kidney and oestrogen-dependent organs such as mammary glands and uterus. The mice of both heterozygous and homozygous genotypes appear to be physically healthy and fertile. Diurnal motility rhythm and behaviour in measuring anxiety and depression were equal in all genotypes. At the age of 12 months, the body weight of homozygous mice was 7-9% lower than that of the other groups. This was reflected in histology as a diminished incidence of vacuolation of liver cells (fatty change). Macroscopic pathology and histopathology revealed no abnormal findings in any COMT genotype. The values of some clinical chemistry parameters, such as alkaline phosphatase, alanine aminotransferase, urea, glucose, calcium and proteins, were at a higher level in homozygous animals compared with the wild-type mice. However, all the values remained within the normal physiological range, and the differences in enzyme levels between genotypes were not reflected as histopathological findings in the relevant organs. No changes in haematological parameters or plasma catecholamine concentrations were noted but plasma 3,4-dihydroxyphenylethylene glycol levels were high in COMT null mice. The results suggest that the full or 50% lack of Comt gene as such is not associated with any toxic consequences.

Aging↗
PubMed2003

Advances in the pharmacological management of Parkinson disease.

Numerous advances have taken place in the pharmacological management of Parkinson disease (PD) in recent years. Some of the more clinically relevant will be discussed in the text that follows. New drugs have been developed to treat or prevent the motor fluctuations and dyskinesias that occur frequently with the continuous use of levodopa. Such drugs include the catechol-O-methyl-transferase (COMT) inhibitors, such as tolcapone and entecapone, and new dopamine (DA) agonists with long half lives such as cabergoline, pramipexole or ropirinole. Also new, atyical, antipsychotics have appeared which have revolutionized the treatment of PD since they allow us to control hallucinations and other psychotic behaviour without worsening of motor function. Finally preliminary reports suggest that cholinesterase inhibitors, such as rivastigmine, can be usefull in the management of cognitive impairment in PD, one of the most difficult clinical problems encountered in the management of this neurodegenerative disorder.

Antiparkinson Agents↗
PubMed1999

Parkinson's Disease: Motor Fluctuations.

Motor fluctuations represent important late complications of Parkinson's disease treated with levodopa. Although treatment of these problems has improved with the emergence of numerous pharmacologic and surgical therapies, the various options can make it confusing. Pharmacologic treatment is the first step. Polytherapy is often the rule in this case with a variety of agents available as adjunctive therapy with levodopa. These adjuncts include dopamine agonists (bromocriptine, pergolide, pramipexole, ropinirole), catechol-O-methyltransferase (COMT) inhibitors (tolcapone), controlled-release formulations of levodopa, monoamine oxidase (MAO) B inhibitors (selegiline), and amantadine. The treatment can consist of any of a number of combinations of these agents. No single algorithm can be used in all patients; therapy should be individualized. Physicians treating these patients need to be well versed in late complication patterns as well as the medications chosen. In addition, optimal doses vary, and often patients are considered treatment failures and taken off medications before reaching that level. In the more complicated cases, patients should be evaluated by specialists in movement disorders. With this in mind, some guidelines are offered for the pharmacologic approach to patients with fluctuating responses to medications. For simple wearing off, controlled-release levodopa (Sinemet CR, Dupont Pharmaceuticals, Wilmington, DE), COMT inhibitors, MAO inhibitors, and dopamine agonists are reasonable options. For more complicated fluctuations, dopamine agonists with limits on levodopa are the first choice, especially when dyskinesia is present; when dyskinesia is not a factor, COMT inhibitors may be used. For dyskinesia specifically, dopamine agonists or addition of amantadine can be helpful. Surgery should be a treatment of last resort for patients in whom medical therapy fails. Patients who are candidates for medial pallidotomy should be fluctuators with severe dyskinesia and "off" periods that have not improved with pharmacologic therapy. Thalamic deep brain stimulation (DBS) should be used only in patients with tremor-predominant disease and severe intractable tremor that is unresponsive to medication and occurs not only at rest but with posture and action as well. Surgical therapy should be performed only in centers with surgeons experienced in stereotactic techniques and movement disorder specialists to ensure that the appropriate patients come to surgery and that complications are kept to a minimum. Dietary adjustment has a limited role in treating advanced Parkinson's disease.

Journal Article↗
PubMed2005

Rapid simultaneous determination of metabolic clearance of multiple compounds catalyzed in vitro by recombinant human UDP-glucuronosyltransferases.

The purpose of this study was to test the applicability of n-in-one (cocktail) incubations in the determination of intrinsic clearance (Cl(int)) as the slope of the linear portion of the Michaelis-Menten curve (velocity V vs. substrate concentration [S]) where substrate concentrations were low. A rapid, sensitive, and selective liquid chromatography tandem mass spectrometry (LC/MS/MS) method was developed for the analysis of samples produced by single-substrate and n-in-one (seven substrates: entacapone, 17beta-estriol, umbelliferone, 4-methylumbelliferone, tolcapone, hydroxyquinoline, and paracetamol) incubations conducted in 96-well plates with different recombinant UDP-glucuronosyltransferases (UGTs). The Cl(int) values obtained with n-in-one incubations were compared with those obtained in single-compound incubations and with V(max)/K(m) values determined by estimating the enzyme kinetic parameters V(max) and K(m) from the Michaelis-Menten curve. When substrate concentrations were well below their K(m) values, Cl(int) values determined as the slope of the linear part of the Michaelis-Menten fitting correlated well with the values determined as V(max)/K(m) ratios from the Michaelis-Menten curve. The correlation between Cl(int) values determined in single-substrate and n-in-one incubations was high as well. Together, the n-in-one incubations, the determination of Cl(int) values as the slope of the linear part of the Michaelis-Menten fitting, and LC/MS/MS as an analytical method proved to be effective approaches for increasing throughput in the first-phase screening of metabolic properties.

Catechols↗
PubMed2002

Mechanisms of idiosyncratic drug reactions: the case of felbamate.

Idiosyncratic drug reactions (IDR) are a specific type of drug toxicity characterized by their delayed onset, low incidence and reactive metabolite formation with little, if any, correlation between pharmacokinetics or pharmacodynamics and the toxicological outcome. As the name implies, IDR are unpredictable and often result in the post marketing failure of otherwise useful therapies. Examples of drugs, which have failed as a result of IDR in recent years, include trovafloxacin, zileuton, troglitazone, tolcapone and felbamate. To date there exists no pre-clinical model to predict these adverse drug reactions and a mechanistic understanding of these toxicities remains limited. In an attempt to better understand this class of drug toxicities and gain mechanistic insight, we have studied the IDR associated with a model compound, felbamate. Our studies with felbamate are consistent with the theory that compounds which cause IDR undergo bioactivation to a highly reactive electrophilic metabolite that is capable of forming covalent protein adducts in vivo. In additon, our data suggest that under normal physiological conditions glutathione plays a protective role in preventing IDR during felbamate therapy, further emphasizing a correlation between reactive metabolite formation and a toxic outcome. Clinical studies with felbamate have been able to demonstrate an association between reactive metabolite formation and a clinically relevant toxicity; however, additional research is required to more fully understand the link between reactive metabolite formation and the events which elicit toxicity. Going forward, it seems reasonable that screening for reactive metabolite formation in early drug discovery may be an important tool in eliminating the post-marketing failure of otherwise useful therapies.

Aldehyde Dehydrogenase↗
PubMed1999

Interaction between L-DOPA and 3-O-methyl-L-DOPA for transport in immortalised rat capillary cerebral endothelial cells.

The present study aimed to determine the kinetics of L-3,4-dihydroxyphenylalanine (L-DOPA) uptake in an immortalised cell line of rat capillary cerebral endothelial cells (clones RBE 4 and RBE 4B), to define the type of interaction with 3-O-methyl-L-DOPA (3-OM-L-DOPA), sensitivity to 2-aminobicyclo(2,2,1)-heptane-2-carboxylic acid (BHC), N-(methylamino)-isobutyric acid (MeAIB) and sodium. Non-linear analysis of the saturation curves for L-DOPA and 3-OM-L-DOPA revealed in RBE 4 cells Km values (in microM) of 72 (53, 91) and 40 (25, 57) and in RBE 4B cells Km values (in microM) of 60 (46, 74) and 44 (13, 75), respectively. IC50 values for 3-OM-L-DOPA (RBE 4, 642 [542, 759] microM; RBE 4B, 482 [475, 489] microM) obtained in the presence of a nearly saturating (250 microM) concentration of L-DOPA were greater than the corresponding Ki values (RBE 4, 143 [121, 170] microM; RBE 4B, 93 [92, 95] microM) obtained in the presence of a nearly saturating (250 microM) concentration of 3-OM-L-DOPA; this is compatible with a competitive type of interaction between L-DOPA and 3-OM-L-DOPA. Uptake of both L-DOPA and 3-OM-L-DOPA in RBE 4 and RBE 4B cells was sensitive to BHC with similar IC50 values. MeAIB (up to 2.5 mM) was found not to interfere with the uptake of both L-DOPA and 3-OM-L-DOPA. Uptake of (250 microM) L-DOPA and 3-OM-L-DOPA in the absence of sodium in the incubation medium was similar to that observed in the presence of increasing concentrations of sodium (20-140 mM). Homogenates of both cell lines were endowed with considerable COMT activity. Incubation of RBE 4 and RBE 4B cells with L-DOPA (25 microM) in the presence of a methyl donor (S-adenosyl-L-methionine) resulted in the formation of 3-OM-L-DOPA; this was abolished by 1 microM tolcapone. The fractional outflow of intracellular L-DOPA through the luminal and abluminal cell side was not affected by the presence of intracellular 3-OM-L-DOPA. The fractional outflow of exogenous 3-OM-L-DOPA applied from the luminal cell border was similar to that observed for 3-OM-L-DOPA with origin in L-DOPA. It is concluded that RBE 4 and RBE 4B cells are endowed with the L-type amino acid transporter through which L-DOPA and 3-OM-L-DOPA can be taken up, and 3-OM-L-DOPA behaves as a competitive inhibitor for the uptake of L-DOPA. This, however, only occurs for luminal cell inward movement but not for abluminal cell outward movement of the substrates.

Amino Acids↗
PubMed2001

Quantitation of entacapone glucuronide in rat plasma by on-line coupled restricted access media column and liquid chromatography-tandem mass spectrometry.

A column-switching liquid chromatography-electrospray ionization-tandem mass spectrometric (LC-ESI-MS-MS) method was developed for the direct analysis of entacapone glucuronide in plasma. The plasma samples (5 microl) were injected onto a C18-alkyl-diol silica (ADS) column and the matrix compounds were washed to waste with a mixture of 20 mM ammonium acetate solution at pH 4.0-acetonitrile (97:3). The retained analyte fraction containing (E)- and (Z)-isomers of glucuronides of entacapone and tolcapone glucuronide (internal standard) was backflushed to the analytical C18 column, with a mixture of 20 mM ammonium acetate-acetonitrile (85:15) for the final separation at pH 7.0. The eluate was directed to the mass spectrometer after splitting (1:100). The mass spectrometer was operated in the negative ion mode and the deprotonated molecules [M-H]- were chosen as precursor ions for the analytes and internal standard. Collisionally induced dissociation of [M-H] in MS-MS resulted in loss of the neutral glucuronide moiety and in the appearance of intensive negatively charged aglycones [M-H-Glu]-, which were chosen as the product ions for single reaction monitoring. Quantitative studies showed a wide dynamic range (0.0025-100 microg/ml) with correlation coefficients better than 0.995. The method was repeatable within-day (relative standard deviation, RSD<7%) and between-day (RSD<14%) and the recovery (78-103%) was better than with the traditional, laborious pretreatment method. The use of tandem mass spectrometry permitted low limits of detection (1 ng/ml of entacapone glucuronide). The method was applied for the quantitation of (E)- and (Z)-isomers of entacapone glucuronide in plasma of rats used in absorption studies.

Animals↗
PubMed2001

Approaching disturbed sleep in late Parkinson's Disease: first step toward a proposal for a revised UPDRS.

A patient in stage 3-4 of the Unified Parkinson's Disease Rating Scale (UPDRS), or in stage 4-5 of Hoehn and Yahr staging scale, or a patient with 0-50% activities of daily living scale of Schwab and England is considered a Late Parkinson's Disease (LPD) patient. The prevalence of disturbed sleep in Parkinson's Disease (PD) was found to vary according to an objective rating, from 60 to 98%. The factors predicting the quality of life in PD patients are: depression, sleep disturbances and dependence. The present article proposes the insertion of the following items as a chapter in a revised UPDRS based on updated knowledge in sleep arousal disturbances in PD. V. SLEEP-AROUSAL DISTURBANCES: Sleep disturbances 43. Light fragment sleep (LFS) 44. Sleep-related breathing disorders (SRBD) 45. Restless legs-periodic leg movements during sleep (RLS-PLM) 46. REM behavioral disorders (RBD) 47. Sleep-related hallucinations (SRH) 48. Sleep-related psychotic behavior (SRPB) Arousal disturbances 49. Sleep attacks (SA) 50. Excessive daytime sleepiness (EDS). Approaching the treatment of disturbed sleep in LPD means postponement of the institutionalization of the LPD patient, allowing the spouse or the caregiver a quiet nights sleep. This approach consists of three steps, each one of major importance. (1) Correct diagnosis based on detailed anamnesis of the patient, of the spouse or of the caregiver; a one week recording on a symptom diary (log) by the patient or the caregiver; excluding co morbidities. Then choosing the most appropriate sleep test, if necessary: polysomnography (PSG), multiple sleep latency test (MSLT), multiple wake latency test (MWLT), actigraphy or video-PSG. This first step allows the diagnosis of one of the above mentioned sleep-arousal disturbances. (2) The non-specific therapeutic approach consists of: (a) checking the sleep effect on motor performance: beneficial, worse or neutral. (b) Dopaminergic adjustment is necessary due to the progression of the nigrostriatal degeneration and the increased sensitivity of the terminals which alter the normal modulator mechanisms of motor centers in LPD patients. Among the many neurotransmitters of the nigro-striatal pathway one can distinguish two with a major influence on REM and non-REM sleep. REM sleep corresponds to an increased cholinergic receptor activity and a decreased dopaminergic activity. This is the reason why REM sleep deprivation by suppressing cholinergic receptor activity ameliorates LPD motor symptoms. L-Dopa and its agonists by suppressing cholinergic receptors suppress REM sleep. L-Dopa has also an arousal effect on Non-REM sleep, repeatedly awakening the patient and enhancing the fragmentation due to the involuntary movements. (c) Socio-physical assistance. (3) The specific therapy consists of: LFS-Sinemet CR, Tolcapone, Intranasal Desmopressin, Domperidon, Cisapride and neurosurgery; SRBD-CPAP, UPPP, nasal interventions, losing weight; RLS-PLM-Benzodiazepine (Clonazepam), Opioid, Apomorphine infusion; RBD-Clonazepam and dopaminergic agonists; SRH-Clozapine, Risperidone; SRPD-Nortriptyline, Clozapine, Olanzepine; SA-adjustment; EDS-arousing drugs. Each therapeutic approach must be tailored to the individual LPD patient.

Antiparkinson Agents↗
PubMed2002

Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase.

A homologous series of novel nitro-catechol structures (7a-7e) were synthesized and tested as inhibitors of the enzyme catechol-O-methyltransferase (COMT). Increasing chain length was found to have significant impact on both brain penetration and duration of COMT inhibition in the rat. Of this series, compound 7b (1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone) was found to exhibit the most potent and selective inhibition of peripheral COMT, with an inhibition profile more similar to entacapone 2 than tolcapone 1 (an equipotent peripheral and central inhibitor) but with much improved duration of action (7b, 70% inhibition and 2, 25% inhibition at 9 h after administration). The effects of structural modifications to 7b on COMT inhibitory profile were investigated, and it is concluded that the carbonyl group and preferably unsubstituted aromatic ring are essential features to maintain prolonged peripheral COMT inhibition. The introduction of the alpha-methylene group, the major structural difference between 7b and 1, would appear responsible for the observed enhancement in selectivity of peripheral COMT inhibition of 7b, which has more limited access to the brain than 1.

Acetophenones↗
PubMed2004

Synthesis, biological evaluation, and molecular modeling studies of a novel, peripherally selective inhibitor of catechol-O-methyltransferase.

A novel series of potent, peripherally selective, and long-acting inhibitors of catechol-O-methyltransferase (COMT) has been synthesized. The introduction and nature of heteroatom-containing substituents to the side-chain of the nitrocatechol pharmacophore was found to have a profound effect on both peripheral selectivity and duration of COMT inhibition in the mouse. This approach led to the discovery of 1-(3,4-dihydroxy-5-nitrophenyl)-3-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]-1-propanone hydrochloride 35 (BIA 3-335), which was found to possess a superior inhibitory profile in vivo over both the nonselective inhibitor tolcapone 1 and the peripherally selective but short-acting entacapone 2. In this model, 35 retained 75% inhibition of peripheral COMT at 6 h after oral administration, yet significantly, only a minor reduction of central (cerebral) COMT activity was observed. Molecular modeling techniques were applied to review the analysis of the ternary enzyme-inhibitor complex previously determined by X-ray crystallography and to provide a deeper understanding of the structure-activity relationships within this novel series. Furthermore, a computational approach was applied in an effort to elucidate the particular structural factors relevant to the poor blood-brain permeability of 35. In conclusion, the improved biological properties herein reported reveal 35 as a candidate for clinical studies as an adjunct to L-DOPA therapy for Parkinson's disease.

Animals↗
PubMed2005

Oxidative stress mediated idiosyncratic drug toxicity.

The following describes a novel screening method for "new chemical entities" (NCEs), suitable for ADMET studies, that measures ability to form prooxidant radicals on metabolism and their ability to induce oxidative stress in intact cells. The accelerated molecular cytotoxic mechanism screening (ACMS) techniques used with isolated rat hepatocytes showed that cytotoxicity is usually initiated as a result of macromolecular covalent binding or macromolecular oxidative stress. While P450 is likely responsible for drug metabolic activation in the liver, intestine, lung, and in other nonhepatic tissues, where P450 levels are low, peroxidases including prostaglandin synthetase peroxidase can catalyze xenobiotic one-electron oxidation to form prooxidant free radicals that may cause toxicity or carcinogenesis. Inflammation markedly activates H2O2, generating NADPH oxidase and peroxidase of certain immune cells when they infiltrate tissues including the liver. Myeloperoxidase and NADPH oxidase in the Kupffer cells (resident macrophages of the liver) also become activated during inflammation. The addition of noncytotoxic concentrations of peroxidase/H2O2 to the hepatocyte incubate markedly increased drug cytotoxicity and prooxidant radical formation as shown by glutathione or lipid oxidation. Many drugs that have hepato- or gastrointestinal (GI) toxicity problems or were withdrawn from the market for safety problems, e.g., troglitazone, tolcapone, mefenamic acid, diclofenac, and phenylbutazone, were markedly more toxic and prooxidant in this inflammation model system, whereas other drugs, e.g., entacapone, were not toxic in this inflammation model. Some of the idiosyncratic hepatotoxicity responsible for recent drug withdrawals may therefore result from commonplace sporadic inflammatory episodes during drug therapy.

Animals↗
PubMed1999

Drug-induced liver disease.

The past year has seen several additions to the list of drugs that cause hepatic injury. Many of these agents produce fulminant hepatic necrosis and, in some cases, were withdrawn from the market (eg, bromfenac). Other drugs had warnings placed in their labeling along with stringent monitoring guidelines to alert physicians and patients alike to the potential for severe hepatic injury (eg, troglitazone, tolcapone). New reports of hepatoxicity continued to appear for many older agents, in some cases expanding the hepatotoxic spectrum for the drugs. Vanishing bile duct syndrome has drawn increasing attention and is now associated with more than 30 drugs. Ibuprofen is among those drugs newly described as causing this syndrome. Hepatitis C virus infection was reported as a possible risk factor for ibuprofen hepatotoxicity, raising the issue of safe use of nonprescription as well as prescription drugs in patients with underlying liver disease. Reports have appeared about acetaminophen-induced hepatotoxicity in several dozen children from unintentional overdoses, in addition to cases of therapeutic misadventure in adults.

Journal Article↗