Lactam Metabolite Research Articles

Identified Synthesis and In-vivo Study of Oxidized Metabolites of Rimonabant via LC-ESI-MS Technique

The convenient oxidation was carried out to Rimonabant and its analogue with mCPBA for the formation of their reactive biological metabolites. The lactam oxidized Rimonabant metabolite was first successfully synthesized for demonstrating the construction and characterized by NMR spectroscopic methods and the single-crystal X-ray diffraction study. Through metabolism study of Rimonabant in vivo in mice, the lactam metabolite belongs to one of many high levels of reactive oxidized Rimonabant metabolites. On the other hand, the lactam metabolite is the most stable form in snapshot PK test and displays markedly reduced brain penetrance.

In-line formation and identification of toxic reductive metabolites of aristolochic acid using electrochemistry mass spectrometry coupling

Small-molecule metabolism has been extensively studied in the past decades, notably driven by the development of new pharmaceutical ingredients. The understanding of metabolism is critical to the anticipation of reactive metabolite formation in vivo that is often associated with toxicity. Electrochemistry has been proposed to simulate the oxidoreductive metabolism reaction catalyzed by cytochrome P450, a family of microsomal enzymes strongly involved in xenobiotic metabolism. The implementation of an electrochemical cell online with mass spectrometry allows for the fast formation and identification of the reaction end products. This study discusses the ability of the synthetic electrochemical approach to simulate a complex lactamization reaction that involves the formation of reactive metabolites. Aristolochic acid I was used as a model molecule to evaluate the ability of electrochemical simulation to generate nitroso, hydroxylamine, N-hydroxylactam, lactam, and nitrenium ion metabolites.

Open-Label Single-Dose Study to Assess the Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics of Mirogabalin

Mirogabalin is an α2δ ligand being developed to treat neuropathic pain. A small fraction of mirogabalin is metabolized by the liver, where hepatic impairment may affect exposure. The objective of this phase I, open-label single-dose study was to determine if mild or moderate hepatic impairment alters the pharmacokinetics of mirogabalin. Serial blood samples were collected for determination of maximum observed concentration, time to maximum concentration, and area under the concentration-time curve until the last quantifiable concentration of the active free form (A200-700) and inactive lactam metabolite (A204-4455) of mirogabalin. The A200-700 maximum observed concentration was similar in subjects with mild hepatic impairment but lower in subjects with moderate hepatic impairment vs. control subjects. The A204-4455 maximum observed concentration was lower in subjects with mild and moderate hepatic impairment vs. control groups. The A200-700 area under the concentration-time curve until the last quantifiable concentration was slightly lower in subjects with mild hepatic impairment and slightly higher in subjects with moderate hepatic impairment vs. control subjects. Peak A204-4455 levels were approximately 22% and 31% lower for subjects with mild and moderate hepatic impairment vs. control individuals, respectively. Exposure to A204-4455 was approximately 37% lower in subjects with mild hepatic impairment but unaffected in subjects with moderate hepatic impairment vs. control groups. Two subjects in the mild hepatic impairment group reported a treatment-emergent adverse event of mild somnolence. No serious or severe treatment-emergent adverse events, discontinuations as a result of treatment-emergent adverse events, or deaths were reported. Mild hepatic impairment resulted in lower A200-700 and A204-4455 exposure, while moderate hepatic impairment did not affect A200-700 exposure. Overall, mild-to-moderate hepatic impairment did not have a significant effect on mirogabalin exposure. A single 15-mg dose of mirogabalin was well tolerated by subjects with mild or moderate hepatic impairment.

Abstract CT419: A phase 1 randomized, open-label, 2-sequence, 2-period crossover study of the effect of multiple doses of palbociclib (PD-0332991) on midazolam pharmacokinetics in healthy women of non-childbearing potential

Abstract Introduction: Palbociclib (PD‑0332991) is an oral cyclin‑dependent kinase (CDK) 4/6 inhibitor currently in Phase 2 and Phase 3 clinical trials in multiple oncology indications. In vitro, palbociclib and its active lactam metabolite (PF‑05089326) caused time‑dependent inhibition of CYP3A-mediated midazolam 1’‑hydroxylase and testosterone 6β‑hydroxylase activities. The primary objective of this study is to investigate the effect of multiple doses of palbociclib on the pharmacokinetics of a single oral dose of the sensitive CYP3A4/5 probe substrate midazolam in healthy women of non-childbearing potential. Methods: This was an open label, randomized, 2‑period 2‑sequence study of the effect of multiple oral doses of palbociclib on midazolam pharmacokinetics in 26 healthy female volunteers of non-childbearing potential. Simulations were performed with SimCYP, using the in vitro CYP inhibition data and human pharmacokinetic data for palbociclib from Study A5481001 as inputs, to optimize the duration of dosing and washout periods. Each subject received two treatments (Treatment A = 2 mg oral dose of midazolam alone, Treatment B = 2 mg oral dose of midazolam on Day 7 of an 8-day 125 mg QD palbociclib dose regimen) in a crossover scheme. Subjects were randomized to one of two sequences (Sequence 1 = A→B, Sequence 2 = B→A). In Sequence 2 there was a washout period of no less than 14 days after the last administered dose of palbociclib to ensure that there was no carryover effect of CYP3A inhibition into Period 2. Serial blood sampling for midazolam pharmacokinetics was performed up to 36 hours post-midazolam dose in both periods. Palbociclib pre-dose blood sampling was performed on specified visits to document achievement of steady-state concentrations. Plasma concentrations of midazolam and palbociclib were each measured using validated LC/MS/MS (liquid chromatography- tandem mass spectrometry) methods. Midazolam plasma pharmacokinetic (PK) parameters were estimated using standard non-compartmental methods. Discussion:In general, palbociclib reached steady-state levels prior to co-administration of midazolam, allowing for a worst case assessment of the potential palbociclib-mediated time-dependent CYP3A inhibition. Midazolam geometric mean Cmax and AUCinf values increased 37% and 61%, respectively, when midazolam was co-administered with multiple doses of palbociclib as compared to its administration alone. These results indicate that palbociclib is a weak CYP3A inhibitor following daily 125 mg dosing at steady-state according to the FDA classification. In general, the combination of palbociclib and midazolam were well tolerated with no reported serious adverse events or treatment discontinuations. Reversible neutropenia was reported in 15 out of the 26 subjects. Citation Format: Justin T. Hoffman, Anna Plotka, Melissa O'Gorman, Cho-Ming Loi, Leonid Kirkovsky, Corrado Gallo-Stampino, Diane Wang. A phase 1 randomized, open-label, 2-sequence, 2-period crossover study of the effect of multiple doses of palbociclib (PD-0332991) on midazolam pharmacokinetics in healthy women of non-childbearing potential. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT419. doi:10.1158/1538-7445.AM2014-CT419

Metabolism and disposition of [14C]tivantinib after oral administration to humans, dogs and rats

1. The biotransformation and disposition of tivantinib in humans, dogs and rats was examined after a single oral administration of [14C]tivantinib. Tivantinib constituted no more than one-third of the plasma radioactivity in all species, demonstrating significant contribution of the metabolites to plasma radioactivity. The major circulating metabolites in all species were M4 and M5, hydroxylated metabolites at the benzyl position of the tricyclic ring, accounting for 19.3 and 12.2% of the AUC of the total radioactivity, respectively, in humans.2. The majority of radioactivity was excreted to the feces via bile. Tivantinib was detected at trace levels in urine, feces and bile, demonstrating extensive metabolism prior to biliary excretion and nearly complete tivantinib absorption under fed conditions.3. Seven metabolic pathways were identified for tivantinib and included six oxidations (M4, M5, M7, M8, M9 and M11) and one glucuronidation (M23). The major metabolic and excretory pathways were found to be common among all species. Species differences in the metabolic pathways included lactam metabolite (M8) formation in humans and dehydrogenated metabolite (M11) formation in animals.4. None of the metabolites identified in this work are believed to significantly impact the efficacy or toxicity of tivantinib in humans.

Tripartilactam, a Cyclobutane-Bearing Tricyclic Lactam from a Streptomyces sp. in a Dung Beetle’s Brood Ball

Tripartilactam, a structurally unprecedented cyclobutane-bearing tricyclic lactam metabolite, was discovered from Streptomyces sp. isolated from a brood ball of the dung beetle, Copris tripartitus. The structure of this compound was elucidated by the combination of NMR, MS, UV, and IR spectroscopy and multistep chemical derivatization. Tripartilactam was evaluated as a Na(+)/K(+) ATPase inhibitor (IC(50) = 16.6 μg/mL).

Effects of the triple reuptake inhibitor amitifadine on extracellular levels of monoamines in rat brain regions and on locomotor activity

Major depressive disorder is a prevalent disease, and current pharmacotherapy is considered to be inadequate. It has been hypothesized that a triple reuptake inhibitor (TRI) that activates dopamine (DA) neurotransmission in addition to serotonin and norepinephrine (NE) circuitries may result in enhanced antidepressant effects. Here, we investigated the pharmacological effects of a serotonin-preferring TRI-amitifadine (EB-1010, formerly DOV 21947). The effects of amitifadine (10 mg/kg ip.) on extracellular concentrations of monoamines and their metabolites in rat brain regions were investigated using the in vivo microdialysis technique. The effects of amitifadine on locomotor activity and stereotyped behavior were also evaluated. A major metabolite of amitifadine, the 2-lactam compound, was investigated for inhibition of monoamine uptake processes. Amitifadine markedly and persistently increased extracellular concentrations of serotonin, NE, and DA in prefrontal cortex. The extracellular concentrations of DA were also increased in the DA-rich areas striatum and nucleus accumbens. The extracellular concentrations of the metabolites of serotonin, 5-hydroxyindoleacetic acid, and DA, 3,4-dihydroxyphenylacetic and homovanillic acid, were also markedly decreased in brain regions. Amitifadine did not increase locomotor activity or stereotypical behaviors over a broad dose range. The lactam metabolite of amitifadine weakly inhibited monoamine uptake. Thus, amitifadine increased extracellular concentrations of serotonin, NE, and DA, consistent with TRI. Although amitifadine significantly increased DA in the nucleus accumbens, it did not induce locomotor hyperactivity or stereotypical behaviors. The enhancement of serotonin, NE, and DA in rat brain regions associated with depression suggest that amitifadine may have novel antidepressant activity.

The failure of substrate pKa to influence the microsomal formation of amides from N-benzylamines: the microsomal metabolism of N-benzyl pyrrolidine, N-benzyl carbazole and N-acetyl-N-benzyl-4-methylaniline.

The in-vitro hepatic microsomal metabolism of N-benzylpyrrolidine (NBP), N-benzylcarbazole (NBC) and N-acetyl-N-benzyl-4-methylaniline (NANBMA) has been studied, using hamster microsomal preparations, to establish whether the corresponding amide is formed. Amide formation was not observed with any of the substrates utilized, although several metabolic products were detected by HPLC with UV detection. These included the oxidative debenzylation products (for all substrates), ring hydroxylated products (for NBC) and a lactam metabolite (for NBP). The results support the concept that the metabolic conversion of benzylic amines to the corresponding amide involves an N-oxidative step.

Pharmacokinetics of moclobemide in male, virgin female, pregnant and nursing rats.

The disposition of moclobemide, a reversible inhibitor of monoamine oxidase isoenzyme A was studied in male, virgin female, pregnant and nursing rats. The average clearance in control rats (male and female) was 36 mL min-1 kg-1, the initial volume of distribution 1.4 L kg-1, the volume of distribution at steady state 2.3 L kg-1 and the terminal half-life 59 min. The blood-to-plasma concentration ratio of moclobemide was 0.84 giving rise to an average blood clearance of 30 mL min-1 kg-1. The clearance values in rats were higher than in man but as a fraction of hepatic blood flow were similar (36 vs 45%). The volume of distribution at steady state was approximately twice as high as in man while the half-life was similar. Pregnant and nursing rats showed no statistically significant differences in their disposition parameters for moclobemide compared with virgin female rats. Nursing rats had statistically significantly lower concentrations of the moclobemide N-oxide metabolite than did pregnant and control rats. Generally lower concentrations of the lactam metabolite were also found in this group although the differences did not reach statistical significance. Moclobemide as well as the N-oxide and lactam metabolites were found in the amniotic fluid suggesting that moclobemide is capable of crossing the placental barrier.

ChemInform Abstract: Synthesis of the Piperidinone Metabolites of Piperidine Type Phenothiazine Antipsychotic Drugs via Ruthenium Tetroxide Oxidation.

The lactam metabolites of the piperidine type phenothiazine antipsychotic drugs thioridazine, mesoridazine and sulforidazine were synthesized in six steps from commercially available 2-(2-hydroxyethyl)piperidine. The key step involved ruthenium tetroxide oxidation of N-protected 2-(2-chloroethyl)piperidine. The products were then oxidized to obtain the phenothiazine ring 5-sulfoxide analogues.

In Vitro Metabolism of the Analgesic Bicifadine in the Mouse, Rat, Monkey, and Human

The in vitro metabolism of [(14)C]bicifadine by hepatic microsomes and hepatocytes from mouse, rat, monkey, and human was compared using radiometric high-performance liquid chromatography and liquid chromatography/tandem mass spectrometry. Two main metabolic pathways were identified in all four species. One pathway was an NADPH-dependent pathway in which the methyl group was oxidized to form a hydroxymethyl metabolite (M2). Its formation was inhibited in human microsomes only by quinidine, a CYP2D6 inhibitor. In incubations with individual cDNA-expressed human cytochromes P450, M2 was formed only by CYP2D6 and CYP1A2, with CYP2D6 activity 6-fold greater than that of CYP1A2. M2 was oxidized further to the carboxylic acid metabolite (M3) by hepatocytes from all four species. The second major metabolic pathway was an NADPH-independent oxidation at the C2 position of the pyrrolidine ring, forming a lactam metabolite (M12). This reaction was almost completely inhibited in human hepatic microsomes and mitochondria by the monoamine oxidase (MAO)-B-specific inhibitor selegiline. Clorgyline, a specific inhibitor of MAO-A, was less effective in inhibiting M12 formation. Other metabolic pathways of variable significance among the four species included the formation of carbamoyl-O-glucuronide, hydroxymethyl lactam, and carboxyl lactam. Overall, the data indicate that the primary enzymes responsible for the primary metabolism of bicifadine in humans are MAO-B and CYP2D6.

SPECIES DIFFERENCES IN METABOLISM AND PHARMACOKINETICS OF A SPHINGOSINE-1-PHOSPHATE RECEPTOR AGONIST IN RATS AND DOGS: FORMATION OF A UNIQUE GLUTATHIONE ADDUCT IN THE RAT

The pharmacokinetics and metabolism of 1-(4-((4-phenyl-5-trifluoromethyl-2-thienyl)methoxy)benzyl)azetidine-3-carboxylic acid (MRL-A), a selective agonist for the sphingosine-1-phosphate 1 (S1P1) receptor, were investigated in rats and dogs. In both species, more than 50% of the dose was excreted in bile. Specific to the rat, and observed in bile, were a taurine conjugate of MRL-A and a glucuronide conjugate of an azetidine lactam metabolite. In dogs, a smaller portion of the dose (54% of administered dose) was excreted intact in bile, and the major metabolites detected were an azetidine N-oxide of MRL-A and an acylglucuronide of an N-dealkylation product. This latter metabolite was also observed in rat bile. Stereoselective formation of the N-oxide isomer was observed in dogs, whereas the rat produced comparable amounts of both isomers. The formation of a unique glutathione adduct was observed in rat bile, which was proposed to occur via N-dealkylation, followed by reduction of the putative aldehyde product to form the alcohol, and dehydration of the alcohol to generate a reactive quinone methide intermediate. Incubation of a synthetic standard of this alcohol in rat microsomes fortified with reduced glutathione or rat hepatocytes resulted in formation of this unique glutathione adduct.

(753): Single-dose and repetitive-dose bicifadine pharmacokinetics in healthy adult male human subjects

Bicifadine is a novel non-opioid analgesic whose neurochemical actions involve the modulation of monoaminergic neurotransmitters pathways involved in pain. The compound has shown activity in chronic back pain and in acute nociceptive pain. Pharmacokinetic profiles of bicifadine and its lactam metabolite have been studied in healthy adult male human subjects following single doses of 200mg and 400mg and during multiple dose regimens of 200mg BID, 200mg TID, and 400mg BID for 8 days (10 per dose group). Plasma concentration time course data were collected over a 24-hour period following single-doses and across dosing intervals on Days 1, 4, and 8 during repetitive dosing. Pharmacokinetic metrics were estimated following noncompartmental data analysis. Peak exposures (Cmax) were achieved at a tmax of approximately 1.5 to 1.8h following single-doses and 1.8 to 2.2h during repetitive dosing. Plasma concentrations increased in a linear manner across the 200mg and 400mg single doses. Linearity was further evidenced by relatively constant apparent oral clearance and mean residence times across doses. Repetitive dosing for 8 days resulted in accumulation ratios [R] of approximately 1.2 for BID dosing and 1.8 for TID dosing. Substantial increases in volume of distribution between the 200mg (V/F= 185 & 182L) and 400mg (V/F= 280L) were observed but not readily explained. Apparent terminal half-life (t1/2) values across single doses (t1/2= 2.6 & 3.4h at 200mg; t1/2= 4.6h at 400mg) were within the limits of variability. Overall, the pharmacokinetic profile of bicifadine was well behaved and inter-individual variability was modest. Steady-state is clearly established within 4 days of BID or TID dosing. Profiles of the lactam metabolite followed a similar trend. Bicifadine is a novel non-opioid analgesic whose neurochemical actions involve the modulation of monoaminergic neurotransmitters pathways involved in pain. The compound has shown activity in chronic back pain and in acute nociceptive pain. Pharmacokinetic profiles of bicifadine and its lactam metabolite have been studied in healthy adult male human subjects following single doses of 200mg and 400mg and during multiple dose regimens of 200mg BID, 200mg TID, and 400mg BID for 8 days (10 per dose group). Plasma concentration time course data were collected over a 24-hour period following single-doses and across dosing intervals on Days 1, 4, and 8 during repetitive dosing. Pharmacokinetic metrics were estimated following noncompartmental data analysis. Peak exposures (Cmax) were achieved at a tmax of approximately 1.5 to 1.8h following single-doses and 1.8 to 2.2h during repetitive dosing. Plasma concentrations increased in a linear manner across the 200mg and 400mg single doses. Linearity was further evidenced by relatively constant apparent oral clearance and mean residence times across doses. Repetitive dosing for 8 days resulted in accumulation ratios [R] of approximately 1.2 for BID dosing and 1.8 for TID dosing. Substantial increases in volume of distribution between the 200mg (V/F= 185 & 182L) and 400mg (V/F= 280L) were observed but not readily explained. Apparent terminal half-life (t1/2) values across single doses (t1/2= 2.6 & 3.4h at 200mg; t1/2= 4.6h at 400mg) were within the limits of variability. Overall, the pharmacokinetic profile of bicifadine was well behaved and inter-individual variability was modest. Steady-state is clearly established within 4 days of BID or TID dosing. Profiles of the lactam metabolite followed a similar trend.

In vitro mircosomal metabolism of N-benzyl and N-benzoylnornicotine derivates by rat

The in vitro hepatic microsomal metabolism of N-1'-benzylnornicotine, N-l'-(p-chlorobenzyl)nornicotine, N-1'-benzoylnornicotine and N-1'-(p-chlorobenzoyl) nornicotine was studied using hepatic washed rat microsomal preparations fortified with NADPH. Substrates and their potential metabolites were synthesized, characterised by spectral methods, and separated using a reverse phase HPLC system consisted of a C18 column and a mobile phase composition of acetonitrile: phosphate buffer. Substrates and their potential metabolites were extracted from biological systems with dichloromethane. Metabolites detected were compared with retention times and uv spectra of authentic standards. Metabolic experiments indicated that oxidative dealkylation leading to the formation of nornicotine and the corresponding aldehydes was a major route of metabolism for N-alkylnornicotine substrates. In addition, N-1'-(p-chlorobenzyl)nornicotine produced the corresponding lactam and amide metabolites. N-Acylnornicotines were hydrolysed to nornicotine.

The biotransformation of nitrogen containing xenobiotics to lactams.

The metabolism of nitrogen heterocyclics may lead to lactam formation. In early studies on xenobiotic metabolism lactams were identified as metabolites of nicotine, cyproheptadine, tremorine and prolintane. Now, because of the increasing availability of powerful analytical techniques, there are many instances of lactams being identified as metabolites. Lactam metabolites are formed from either iminium ions or carbinolamines. These two intermediates may have distinct mechanisms of formation but they can interconvert. There is evidence that the iminium ions are oxidized to lactams by aldehyde oxidases (cytosolic molybdenum hydroxylases). The tissue distribution and enzyme activities of aldehyde oxidase have been studied in several animal species. However, it is also known that iminium ions can undergo spontaneous hydrolysis to the corresponding carbinolamine. If the latter is stable it may undergo oxidation by cytochrome P-450 to form the lactam. Thus, species differences in lactam formation might be caused by differences in the concentrations of either cytochrome P450 isozymes or aldehyde oxidases. It appears that lactam formation is an end stage in the metabolism of N-heterocycles in that it is unlikely that the lactam will undergo hydrolysis to the corresponding amino acid. Such amino acids probably arise from the amino aldehydes that may be produced from ring opening of unstable carbinolamine intermediates. When microsomal preparations are incubated with the appropriate substrate in the presence of sodium cyanide the iminium ion may be trapped to produce a cyano compound. Such reactions have led to the proposal that iminium ions might react with nucleophilic sites of cellular macromolecules and so contribute to both the pharmacology and toxicology of N-heterocyclic compounds. Other pathways for the formation of lactam metabolites involve the internal cyclization of precursor metabolites, e.g. the self-condensation of an aldehyde group (formed during metabolism) with a neighboring amide group. However, spontaneous ring closures of amino acids to form lactams seem unlikely since it would be anticipated that the amino acid residue would exist as a stable zwitterion under physiological conditions. Thus, it is unlikely that lactams will undergo futile metabolism via hydrolytic ring opening followed by ring closure. Under extreme conditions such unanticipated ring closures may occur and the conditions of metabolite isolation may contribute to the occurrence of artifacts.

In vitro metabolic N- and C-oxidation of phenanthridine.

The in vitro microsomal metabolism of phenanthridine has been studied to establish as to whether phenanthridine produces the corresponding N-oxide and lactam as metabolites and the mechanism involved. We now report our preliminary findings using rat hepatic microsomal preparations (control and induced with phenobarbitone) fortified with NADPH. The potential metabolite, phenanthridine-N-oxide, was prepared by m-CPBA oxidation of substrate; the lactam was commercially available. The substrate and metabolites were extracted and analysed by HPLC and TLC. Five metabolites, i.e. the corresponding N-oxide, lactam and three other products, were detected. Both N-oxide and lactam metabolites showed identical chromatographic behaviour and UV spectrum--using a multi-array UV detector linked to a HPLC system--as the authentic compounds. The uncharacterised metabolites are proposed to be phenolic because of their chromatographic behaviour and response to detection reagents. The amount of N-oxide and lactam formed was significantly increased when phenobarbitone induced rat microsomes were used as enzyme source. The results indicate that these latter metabolites are probably formed by a phenobarbitone inducible CYP450 isozyme. It may be that the lactam was produced via the N-oxide and experiments are under way to investigate the proposed pathway.

Identification of lactams as in vitro metabolites of piperidine-type phenothiazine antipsychotic drugs

The metabolism of the piperidine-type phenothiazine antipsychotic agents thioridazine, mesoridazine and sulforidazine was studied in vitro with 10 000g liver supernatants obtained from rats and dogs. After incubations at 37°C for different time intervals, the incubates were extracted with dichloromethane and the isolated compounds analyzed by HPLC, direct probe MS and on-line HPLC-MS. Five lactam metabolites of these three drugs were unequivocally identified in the rat in vitro system, but none was found in dog preparations; at least one lactam metabolite was identified for each drug in the rat. The lactams of thioridazine and thioridazine ring sulfoxide were characterized as metabolites of thioridazine for the first time in any system. The other three lactam metabolites, namely the lactams of mesoridazine, sulforidazine and mesoridazine ring sulfoxide, were found in vitro for the first time, although they have been previously reported as in vivo metabolites of these drugs. The results indicate that rat would be a more suitable animal model than dog for further studies on the formation of lactam metabolites of these drugs.

Severe acne-like lesions in chronic amineptine overdose and Hodgkin's lymphoma

We report a case of a male patient with Hodgkin's lymphoma and severe acne-like lesions associated with taking amineptine, a tricyclic antidepressant. The lesions appeared after self-administration of high doses of the drug, up to 4000 mg/day. The relationship between the acne-like lesions, drug intake and lymphoma are discussed. The severity of these cutaneous lesions seems to be correlated with the degree of overdose. A high concentration of lactam metabolites found in the lesions may explain their persistence. Drug addiction and alcoholism seem to be adjunctive risk factors for amineptine side-effects. The effect of amineptine may be facilitated by the presence of Hodgkin's disease.

The metabolism of piperidine-type phenothiazine antipsychotic agents. III. Mescridazine in dog, human and rat

1. The metabolism of mesoridazine was studied in female rats (20 mg/kg, oral), female dogs (50 mg over 30 h, oral) and adult male volunteers (25 mg, oral). 2. Solvent extracts of urines from each species were directly analysed by h.p.l.c.-mass spectrometry with a plasmaspray interface. In the case of phenolic metabolites the urinary extracts were derivatized with a silylating reagent (with and without prior enzymic hydrolysis) prior to analysis. The structures of metabolites, with the exceptions of mesoridazine N-oxide and phenols, were confirmed by comparison of their chromatographic behaviours and mass spectra with those of authentic standards. 3. Compounds identified in the urine of all three species were mesoridazine, sulforidazine, mesoridazine ring sulphoxide, sulforidazine ring sulphoxide, N-desmethylmesoridazine ring sulphoxide, the lactam of sulforidazine ring sulphoxide and phenolic derivatives of mesoridazine and sulforidazine. Whereas the unconjugated phenolic metabolite of sulforidazine was present in urine of all three species, the conjugated form was identified only in dog and rat urines. Also, the unconjugated phenolic metabolite of mesoridazine was identified only in the urine of dog and human, but rat urine contained only the conjugated form. 4. Other metabolites found were: the lactam of mesoridazine (rat), the lactam of mesoridazine ring sulphoxide (rat and human), mesoridazine N-oxide (human) and sulforidazine N-oxide (dog and human). 5. Mesoridazine and six of its metabolites present in urines of human, rat and dog were quantified by a h.p.l.c.-u.v. method. The mean total excretion of measured analytes in human, rat and dog were 6.3, 2.6 and 29.1%, respectively. The excretion of the lactam of sulforidazine ring sulphoxide was greater in human (0.4%) and rat (0.2%) than dog (0.02%). Moreover, the urinary excretion of the lactam of mesoridazine ring sulphoxide in human and rat constituted 0.4% and 0.2%, respectively. Of the three lactams found in rat the lactam of mesoridazine was present in the least amount (0.05%). 6. Interspecies comparison of the lactam metabolites indicated that both qualitatively and quantitatively human more closely resembled rat than dog. On the other hand, N-oxide metabolites were detected in human and dog but not in rat.

The disposition and metabolic fate of 14C-meropenem in man.

1. The metabolism and pharmacokinetics of 14C-meropenem were studied in five volunteers who received 0.5 g (40 microCi) of the radiolabelled drug by i.v. infusion. 2. The maximum concentration of drug in plasma was 27 +/- 2 micrograms/ml (70 microM) corresponding to 98% of plasma radioactivity at the end of a 30 min infusion. The elimination half-life for meropenem in plasma was 1 h and meropenem remained the major radioactive component up to 6 h, but represented a decreasing proportion of the plasma radioactivity with time. One metabolite (the ring-open lactam) accounted for most of the remaining plasma radioactivity. The maximum concentration of metabolite was 1 +/- 0.1 micrograms/ml and the concentration of total radioactivity decreased to 2% of the peak value by 8 h. 3. Over the 5 days of the study, urinary excretion of radioactivity accounted for 99 +/- 0.5% dose, most of which was recovered in the first 8 h. There was negligible excretion in faeces. 4. Structural confirmation of the drug-related components in urine was accomplished by h.p.l.c.-mass spectrometry. Meropenem accounted for 71 +/- 2% dose of 14C and the ring-open lactam metabolite for most of the remainder, no other metabolites were detected. 5. Meropenem was the major radioactive component in urine up to 8 h after dosing and is therefore remarkably stable to human renal dehydropeptidase (DHP-1) compared with other carbapenems in clinical use.