Acetaminophen (paracetamol) is a popular domestic analgesic and antipyretic agent with a weak anti-inflammatory action and a low incidence of adverse effects as compared with aspirin and other non-steroidal anti-inflammatory drugs. Here we show that acetaminophen, following deacetylation to its primary amine, is conjugated with arachidonic acid in the brain and the spinal cord to form the potent TRPV 1 agonist N-arachidonoylphenolamine (AM404). This conjugation is absent in mice lacking the enzyme fatty acid amide hydrolase. AM404 also inhibits purified cyclooxygenase (COX)-1 and COX-2 and prostaglandin synthesis in lipopolysaccharide-stimulated RAW264.7 macrophages. This novel metabolite of acetaminophen also acts on the endogenous cannabinoid system, which, together with TRPV 1 and COX, is present in the pain and thermoregulatory pathways. These findings identify fatty acid conjugation as a novel pathway for drug metabolism and provide a molecular mechanism for the occurrence of the analgesic N-acylphenolamine AM404 in the nervous system following treatment with acetaminophen.Acetaminophen was introduced into clinical medicine more than a century ago, but its mechanism of action is still a matter of debate. The analgesic, antipyretic, and anti-inflammatory effects of non-steroidal anti-inflammatory drugs are believed to depend on their ability to inhibit COX 1 (1, 2). However, acetaminophen differs from most non-steroidal anti-inflammatory drugs in that it is a weak anti-inflammatory agent with a low incidence of COX-related adverse effects (2-4).Although this may seem incompatible with an action on COX, studies in vitro clearly show that acetaminophen is able to inhibit both COX-1 and COX-2, provided that the ambient concentration of peroxides is kept low (5-7). Such a peroxidedependent inhibition of COX could explain why acetaminophen does not suppress inflammation and platelet activity (5-7). However, final proof that the analgesic and antipyretic effects of acetaminophen are dependent on COX is still lacking. There are also indications that the analgesic effect of acetaminophen is mediated by molecular targets distinct from COX (8 -10).In this study we have explored the possibility that acetaminophen undergoes a two-step metabolic transformation to form the bioactive N-acylphenolamine AM404. AM404 is a potent activator of TRPV 1 , a ligand at cannabinoid CB 1 receptors and an inhibitor of cellular anandamide uptake, the inhibition of which leads to increased levels of endogenous cannabinoids (11-15). TRPV 1 and cannabinoid CB 1 receptors are both present in the pain and thermoregulatory pathways, and much interest has been focused on these receptors as potential drug targets for the treatment of pain and inflammation (11, 14, 16 -19).AM404 belongs to a group of bioactive N-acylamines that also includes the endogenous lipids anandamide (20), N-arachidonoyldopamine (21), and N-arachidonoylglycine (22) and the synthetic compounds olvanil (23) and arvanil (24). These drugs all display analgesic activity in a ...

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When Efexor (venlafaxine) became available in Sweden, a therapeutic drug monitoring (TDM) service was developed in the authors' laboratory. This analytical service was available to all physicians in the country. From March 1996, to November 1997, 797 serum concentration analyses of venlafaxine (VEN) and its main metabolites, O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV), and N,O-didesmethylvenlafaxine (DDV) were requested. These samples, each of which was accompanied by clinical information on a specially designed request form, represented 635 inpatients or outpatients, comprising all ages, treated in a naturalistic setting. The first sample per patient, drawn as a trough value in steady state and with documented concomitant medication, was further evaluated pharmacokinetically (n = 187). The doses prescribed were from 37.5 mg/d to 412.5 mg/d. There was a wide interindividual variability of serum concentrations on each dose level, and the mean coefficient of variation of the dose-corrected concentrations (C/D) was 166% for C/D VEN, 60% for C/D ODV, 151% for C/D NDV, and 59% for C/D DDV. The corresponding CV for the ratio ODV/VEN was 110%. However, within patients over time, the C/D VEN and ODV/VEN variation was low, indicating stability in individual metabolizing capacity. Patients over 65 years of age had significantly higher concentrations of C/D VEN and C/D ODV than the younger patients. Women had higher C/D NDV and C/D DDV, and a higher NDV/VEN ratio than men, and smokers showed lower C/D ODV and C/D DDV than nonsmokers. A number of polycombinations of drugs were assessed for interaction screening, and a trend for lowered ODV/VEN ratio was found, predominantly with concomitant medication with CNS-active drug(s) known to inhibit CYP2D6.

There is renewed interest in the clinical use of thalidomide, because of its unique immunomodulating action. Because data on the metabolism of thalidomide in man are very sparse, the aim of this study was to develop HPLC assays for the 5-hydroxy, 5,6-dihydroxy, 4,5-dihydroxy and 5'-hydroxy metabolites of thalidomide and to investigate their possible formation in man-in-vitro in liver homogenates and in-vivo in healthy volunteers. Reversed-phase HPLC assays with UV detection were developed for quantification of the metabolites in the low ng mL(-1) range in plasma and incubate samples. The stability of the metabolites was investigated and degradation was avoided by rapid chilling and acidification of the samples. After incubation of thalidomide with fraction S9 from human liver, formation of the 5-hydroxy and 5'-hydroxy metabolites could be demonstrated. The 5'-hydroxy metabolite was found, in low concentrations, in plasma samples from eight healthy male volunteers who had received thalidomide orally. The other three metabolites could not be found by HPLC with detection limits of 1-2 ng mL(-1). Thus the formation of two hydroxylated metabolites of thalidomide in the liver in man was demonstrated, but only one of these could be detected in the circulation.

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