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Formestane (Lentaron(R), 4-hydroxyandrostenedione) is a steroidal aromatase inhibitor used for treatment of advanced breast cancer. Clinically, it is administered as a depot form once fortnightly by intramuscular (i.m.) injection. To investigate the pharmacokinetics, bioavailability and metabolism of the drug, seven patients received single 250 mg i.m. doses of commercial formestane on Days 0, 21, 35, 49 and 63 of this trial. On Day 63, three of the patients received an additional single intravenous (i.v.) pulse dose of 1 mg of 14C-labelled formestane. The plasma kinetics after i.m. dosing confirmed a sustained release of formestane from the site of injection. Within 24-48 h of the first dose, the circulating drug reached a C(max) of 48.0+/-20.9 nmol/l (mean+/-S.D.; N=7). At the end of the dosing interval, after 14 days, the plasma concentration was still at 2.3+/-1.8 nmol/l. The kinetic variables did not significantly change during prolonged treatment. Intramuscular doses appear to be fully bioavailable. Following i.v. injection of 14C-formestane, the unchanged drug disappeared rapidly from plasma, the terminal elimination half-life being 18+/-2 min (N=3). Plasma clearance, CL was 4.2+/-1.3 l/(h kg) and the terminal distribution volume V(z) was 1.8+/-0.5 l/kg. The drug is mainly eliminated by metabolism, renal excretion of metabolites accounting for 95% of dose. The excretory balance of 14C-compounds in urine and faeces totals up to 98.9+/-0.8% of the i.v. dose after 168 h. The 14C-compounds in plasma and urine were separated by HPLC, and three major metabolites were submitted to structural analysis by MS, NMR and UV spectroscopy. One of the metabolites is the direct 4-O-glucuronide of formestane. The other two represent 3-O-sulfates of the exocons 3beta,4beta-dihydroxy-5alpha-androstane-17-one and 3alpha,4beta-dihydroxy-5alpha-androstane-17-one, their ratio being 7:3. These exocons are formed by stereoselective 3-keto reduction, accompanied by reduction of the 4,5-enol function. The exocons do not inhibit human placental aromatase activity in vitro.

1. The disposition of valsartan, a potent angiotensin II receptor antagonist, was investigated in six healthy male volunteers. They each received a single oral dose of 80 mg of a 14C-labelled preparation as a neutral buffered solution. 2. Peak concentrations of radioactivity and valsartan in plasma measured 1 h after dosing showed rapid onset of absorption. The results of this study combined with other available data indicate that at least 51% of the dose was absorbed. 3. Valsartan was the predominant radioactive compound in plasma. Elimination of valsartan and radioactivity was fast and multiexponential. beta-Half-lives of 6 +/- 1 h were observed. In a terminal elimination phase, low radioactivity levels decreased with a half-life of 81 +/- 33 h. A minor, pharmacologically inactive metabolite (valeryl-4-hydroxy-valsartan; M1) was detected in the plasma at time points later than 2 h after dosing, representing approximately 11% of the AUC(24 h) of plasma radioactivity. 4. The bulk of the dose was excreted within 4 days. The total excretion within 7 days amounted to 99 +/- 1% of dose. Faecal excretion was predominant (86 +/- 5% of dose). Valsartan was largely excreted unchanged (81 +/- 5% of the dose in the excreta). The predominant clearance mechanism appeared to be direct elimination via bile. 5. An inactive metabolite, M1, was formed by oxidative biotransformation and accounted for 9 +/- 3% of the dose in the excreta.

The new antidepressant agent oxaprotiline is extensively metabolized by man. Following an oral 50 mg dose of racemic [14C]oxaprotiline, most of the 14C was excreted in the urine as metabolites (greater than 98% total 14C); only 1% was excreted unchanged. Glucuronidation at the carbinol group of the molecule is the major metabolic pathway (83%). The two diastereoisomeric glucuronides were separated; the more polar O-glucuronide of S(+)-oxaprotiline predominates (44%), suggesting stereoselective disposition of the two enantiomers. Oxidative pathways are minor, and yield desmethyl oxaprotiline (10%) and 3-hydroxy R(-)-oxaprotiline (4%), both of which are conjugated with glucuronic acid. The biotransformation of oxaprotiline in man is less complex than that of other polycyclic antidepressants, which are metabolized mainly by oxidative reactions.

The preparation of a dimethyltetrahtdrouroporphyrin (Faktor II or sirohydrochlorin) using suspensions of Propionibacterium shermanii as well as a promising method for the isolation of tetrapyrrols with at least four carboxy substituents from cell-free extracts and growth media are described. Also a Faktor II-analogue with three methyl groups which are derived from L-methionine is reported. Incorporation experiments indicate that this is an intermediate in cobyrinic acid formation. Because of this, and from spectroscopic (field desorptionmass, visible absorption) studies it is concluded that the "extra" methyl group is located at the meso-carbon between two methylated reduced rings.

1. Among the phenolic metabolites of diclofenac in human plasma, an unknown compound (metabolite VI) was detected by h.p.l.c. and g.c. methods. This was also found in baboon plasma. 2. Metabolite VI was identified as 3'-hydroxy-4'-methoxy diclofenac by mass and n.m.r. spectroscopic analysis. Comparison with synthetic reference compound confirmed its structure. 3. In plasma, metabolite VI persists much longer than do unchanged diclofenac and the other phenolic metabolites. In urine, metabolite VI and its conjugates are excreted in trace amounts only. 4. A synthetic sample of metabolite VI was shown to be virtually inactive in animal models of inflammation and pain.

Clostridium tetanomorphum and Propionibacterium shermanii were examined for intermediates in the synthetic pathway uroporphyrinogen III leads to cobyrinic acid. The isolation of two novel methylated hydroporphyrins, whose methyl groups are derived from S-adenosyl-L-methionine, is described. Spectroscopic (field desorption-mass, visible absorption) und electrophoretic studies as well as incorporation of labelled substrates indicate that they are analogues of a dihyrouroporphyrin and a tetrahydrouroporphyrin with adjacent reduced rings. Field desorption spectra of the [C2H3]- and [CH3]-tetrahydrouroporphyrin analogues show that the compound contains two methyl groups; it is concluded that the chlorine-like compound has one methyl group. Dehydrogenation experiments indicate that the methyl groups are located at one beta-carbon of the reduced rings. Incorporation experiments suggest that the tetrahydrouroporphyrin-like compound is an intermediate in cobyrinic acid biosynthesis. Studies on the utilization of a heptacarboxyporphyrinogen from C. tetanomorphum for cobyrinic acid formation are also described.

The disposition of the new anti-epileptic agent oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) has been studied in two healthy volunteers following an oral 400 mg dose of 14C-labelled drug. The dose was excreted almost completely in the urine (94.6 and 97.1%) within six days. Faecal excretion amounted to 4.3 and 1.9% of the dose in the two subjects. In the 0-6 days urine samples the biotransformation products have been isolated and identified. 10,11-Dihydro-10-hydroxycarbamazepine (GP 47,779) and its two diastereoisomeric O-glucuronides were found as main metabolites. Taken together, they accounted for 79% of urinary 14C. Unchanged oxcarbazepine, and its sulphate and glucuronide conjugates were isolated in smaller amounts only (13%). Other minor metabolites were the trans- and cis-isomers of 10,11-dihydro-10,11-dihydroxy-carbamazepine (approximately 4%), and a phenolic derivative of GP 47,779 (less than 1%). The biotransformation of oxcarbazepine proceeds mainly by reduction to GP 47,779, and subsequent conjugation with glucuronic acid. Reduction is stereospecific, favouring the S-configuration of GP 47,779. Direct conjugation of oxcarbazepine, in the enol form, is a minor pathway. Oxidative reactions are unimportant.

Indoxyl derivatives were detected as minor products among the urinary metabolites of two trial drugs, a benzodiazepine (GP 55 129) and a benzophenone (CGP 11 952). Their structures were elucidated by NMR and mass spectroscopy. Presumably, metabolites containing potential aldehyde functions react spontaneously with endogenous indoxyl. Such derivatives have not hitherto been encountered in drug metabolism.

1. The anti-inflammatory agent diclofenac sodium (o-[(2,6-dichlorophenyl)amino]phenylacetic acid sodium salt) is extensively metabolized by rat, dog, baboon and man. The main metabolites were isolated from the urine of all species and from the bile of rat and dog and identified by spectroscopy. 2. Metabolism involves direct conjugation of the unchanged drug, or oxidation of the aromatic rings usually followed by conjugation. Sites of oxidation are either position 3' or 4' of the dichlorophenyl ring or, alternatively, position 5 of the phenyl ring attached to the acetic acid moiety. 3. In the urine of rat, baboon and man conjugates of the hydroxylated metabolites predominate, but the major metabolite in dog urine is the taurine conjugate of unchanged diclofenac. 4. In the bile of rat and dog, the main metabolite is the ester glucuroniade of unchanged diclofenac.

The biotransformation of oxaprotiline has been investigated in rat and dog after oral administration of racemic 14C-labelled oxaprotiline X HCl. Rats excreted 28% dose in urine within 120 h and dogs 32% within 96 h. The metabolites were isolated by liquid chromatography and their structures elucidated by spectroscopic methods. In both species, oxaprotiline is extensively metabolized. Principal metabolic transformations are aromatic hydroxylations and formation of aromatic hydroxy-methoxy derivatives, N-demethylation, deamination and direct O-glucuronidation. Most of the primary metabolites formed by functionalization reactions occur in both free and glucuronidated form. In the rat, diastereoisomeric 3-hydroxy metabolites and the corresponding phenolic glucuronides are predominant. Products of deamination are minor, and products of direct O-glucuronidation are not detectable. In the dog, biotransformation is more complex. Major metabolites are diastereoisomeric 2- and 3-hydroxy compounds and the corresponding phenolic glucuronides. Oxidations in the side-chain and direct O-glucuronidation are minor metabolic pathways.