Polymer-bound camptothecin: initial biodistribution and antitumour activity studies.

Camptothecin (CPT) is a potent, antitumour drug acting mainly through inhibition of topoisomerase I during the S-phase of the cell cycle. Despite its impressive antitumour activity, clinical development was halted for unpredictable toxic events. Two soluble N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers were synthesised to contain CPT (5 wt.% and 10 wt.%). CPT was covalently linked at its alpha-hydroxyl group to the polymers through a Gly-Phe-Leu-Gly- spacer. In-vitro, CPT-conjugates were fairly resistant to hydrolysis in plasma as in buffer at neutral pH (0.2-0. 4% free CPT/h), while elastase and cysteine-proteases were able to release the active drug. Plasma levels in mice after intravenous administration of CPT-conjugates confirmed the modest hydrolysis in plasma. Plasma levels were approximately 5-fold lower than those observed at the highest tolerated dose of CPT administered in classical vehicles. Biodistribution in HT29 human colon carcinoma bearing mice was carried out after i.v. injection of [3H]CPT-conjugate and free [3H]CPT. Radioactivity uptake in tumour was evident only after [3H]CPT-conjugate treatment. Repeated intravenous administration of CPT-conjugates to HT29-bearing mice gave more than 90% tumour inhibition, some complete tumour regressions and no toxic deaths. The improved pharmacological profile on HT29 human colon carcinoma xenografts of the first poly(HPMA)-CPT conjugates might be ascribed to their prolonged intra-tumour retention and sustained release of the active drug.

Species-differences in disposition and reductive metabolism of methoxymorpholinodoxorubicin (PNU 152243), a new potential anticancer agent.

Plasma pharmacokinetics, excretion balance and urinary metabolites of methoxymorpholino doxorubicin (MMDX) were investigated in male and female rats and in female dogs after i.v. administration of the(14)C-labelled drug. The mean total recovery of radioactivity in 96 h (urine plus faeces) was approximately 74 and 60% dose in male and female rats, respectively, while in female dogs approximately 72% dose was recovered in 336 h. Most of the radioactivity was present in faeces, with the urinary elimination accounting for only 3-4% dose in rats and dogs. These data suggest that biliary excretion is an important route of elimination of MMDX and/or its metabolites in both species. No differences were observed in the urinary metabolic profile of male and female rats. Two main peaks were present in radiochromatograms of urine from rats and dogs, i.e. MMDX and its 13-dihydro metabolite (MMDX-ol), accounting for approximately 25 and 20% of total radioactivity in 0-24-h urine in rats and 30 and 36% in dogs. The MMDX-ol/MMDX ratio in dog urine was higher than that observed in rat urine. No aglycones were detected in the urine samples from either species. In the rat, the plasma concentration-time profile suggested that the disposition of MMDX, MMDX-ol and total radioactivity is not sex-dependent. MMDX was the major species present in the systemic circulation; its AUC (0-96 h) accounted for 70% of total plasma radioactivity with the sum of AUC (MMDX) plus AUC (MMDX-ol) accounting for 77% of total radioactivity. In the dog, the sum of AUC (MMDX) plus AUC (MMDX-ol) amounted to 8% of radioactivity AUC(0-t(z) indicating that an important proportion of other(s) unknown metabolite(s) is present in dog plasma. Plasma levels of MMDX-ol in the rat were approximately 10-fold lower than those of the parent compound, whereas they were three times higher than those of MMDX in the dog. These data show that the reduction of the 13-keto group of MMDX is species-dependent, and occurs preferentially in the dog compared to the rat.

Inducing properties of rifampicin and rifabutin for selected enzyme activities of the cytochrome P-450 and UDP-glucuronosyltransferase superfamilies in female rat liver.

Important species differences have been reported concerning the induction properties of rifampicin towards enzymes of the P-450 superfamily. Mice, rabbits and humans are far more responsive than rats and guinea pigs. In the present study a strong induction of cytochrome P-450 3A-dependent enzyme activities was observed in female rat liver microsomes after high dose treatment (> or = 250 mg/kg/day for 9 days) with rifampicin, resulting in an up to 30-fold enhanced hydroxylation rate of testosterone in the 2 beta-, 6 beta- and 15 beta-position in vitro. Other cytochrome P-450 isozyme-selective reactions were not, or only marginally, affected. A steep increase in cytochrome P-450 3A activity on a moderate elevation of the dose administered, together with the previously observed lack of efficient induction with doses below 200 mg/kg/day demonstrated that there is a threshold in enzyme induction by rifampicin. For rifabutin such a threshold was not apparent. Induction by rifabutin showed an isoenzyme-selectivity profile similar to that produced by rifampicin, but the maximally achievable induction of cytochrome P-450 3A by rifabutin was about two-fold lower compared with rifampicin. Rifampicin and rifabutin enhanced the glucuronidation of 1-naphthol, 4-hydroxybiphenyl and beta-estradiol by a factor of two to three. The potential implications of the enzyme induction by rifampicin derivatives in terms of possible drug-drug interactions are discussed.

Pharmacokinetics of reboxetine in healthy volunteers. Single oral doses, linearity and plasma protein binding.

The pharmacokinetics of reboxetine, a new antidepressant agent, were found to be close to linear in a crossover study comparing administration of single 2, 3, 4, and 5 mg capsule doses in 15 healthy male volunteers, and in the same study the capsules were bioequivalent to the proposed therapeutic tablet formulation (4 mg). Kinetic analysis was based on HPLC assay of reboxetine in plasma and urine collected up to 72 h after each administration. Plasma levels indicated a rapid absorption (tmax approximately equal to 2 h) and an elimination half-life of about 13 h. Clearance and volume of distribution were modest (ratios to bioavailability: CL/F approximately equal to 29 mL min-1; Vz/F approximately equal to 32 L); urinary excretion was approximately 9% of dose, corresponding to a renal clearance of only 3 mL min-1 (a value consistent with the rate of glomerular filtration of unbound drug). In vitro, binding to plasma proteins, estimated from radioactivity levels following dialysis of 14C-labelled reboxetine, appeared to be dominated by alpha 1-acid glycoprotein without marked saturation up to plasma concentrations of over 500 ng mL-1 (2.8-3.1% unbound with human plasma from three additional volunteers; 1.8-2.0% for 2 gL-1 orosomucoid alpha 1-acid glycoprotein, and 46.4-47.4% for 40 g L-1 albumin), whilst the mean Cmax in the current study was much lower (164 ng mL-1 after a 5mg dose).

Stereoselective and species-dependent kinetics of reboxetine in mouse and rat.

Reboxetine, (RS)-2-[(RS)-alpha-(2-ethoxyphenoxy)benzyl]morpholine methanesulphonate, is a racemic compound and consists of a mixture of the (R,R)- and (S,S)-enantiomers. In this study, brain and plasma levels of both enantiomers were determined in mice and rats after oral administration of reboxetine at doses (1.1 mg/kg, mouse; 20 mg/kg, rat) twice the respective ED50 values in the antireserpine test. Plasma and brain concentrations of each enantiomer were measured up to 6 h postdosing using an HPLC method with fluorimetric detection after derivatization with a chiral agent (FLEC). In mice and rats, brain and plasma levels of the (R,R)-enantiomer were always higher than those of the (S,S)-enantiomer. After normalization for dose, the mean AUC0-tz values of both the (R,R)- and (S,S)-enantiomers in mouse brain were about 23 and 32 times higher than in rat brain, respectively. In plasma, the corrected mean AUC0-tz values were about 5 (R,R) and 10 (S,S) times higher in mice than in rats. These results provide evidence for the higher bioavailability and/or lower clearance of both enantiomers in mice than in rats, and for a higher penetration of both enantiomers into mouse brain compared to rat brain.

The anticonvulsant FCE 26743 is a selective and short-acting MAO-B inhibitor devoid of inducing properties towards cytochrome P450-dependent testosterone hydroxylation in mice and rats.

The effects of the potent anticonvulsant FCE 26743 ((S)-2-(4-3-fluorobenzyloxy)benzylamino)propionamide) on monoamine oxidase (MAO) activity were measured in-vitro and ex-vivo using rat tissue homogenates. In-vitro, FCE 26743 showed potent and selective inhibitory properties towards liver MAO-B, with IC50 values about 10(-7) M for MAO-B and higher than 10(-5) M for MAO-A. When determined ex-vivo in brain, the ED50 value for the inhibition of MAO-B was 1.1 mg kg-1 (p.o.) 1 h post-dosing, whereas MAO-A remained virtually unaffected after administration of 60 mg kg-1. Similar effects were seen in liver. Following oral administration of 5 mg kg-1 FCE 26743 to rats, brain MAO-B inhibition was 79% after 1 h and 13% after 24 h, indicating that FCE 26743 behaves as a short-acting MAO-B inhibitor. The ability of FCE 26743 to act as a MAO substrate was assessed in mice by measuring the urinary excretion of alaninamide, a potential metabolite of FCE 26743 which would result from the action of MAO. No alaninamide was detectable in the 0-8 h urines after administration of a 119 mg kg-1 dose, suggesting that FCE 26743 is not, or only to a small degree, a substrate of MAO. The effects of FCE 26743 on cytochrome P450 enzymes involved in testosterone hydroxylation were determined in rats after repeated administration. No induction of the cytochrome P450 system was noted.

Reboxetine prevents the tranylcypromine-induced increase in tyramine levels in rat heart.

This study aimed to examine whether the increase in heart radioactivity levels after intravenous injection of 14C-tyramine to rats pretreated with the irreversible MAO inhibitor tranylcypromine could be antagonized by reboxetine, a potent and selective noradrenaline uptake blocker. Reboxetine was found totally to abolish the effect of tranylcypromine. Heart radioactivity levels after reboxetine and tranylcypromine were very similar to those found when tyramine was injected after reboxetine only. These results suggest that reboxetine might be advantageously combined with tranylcypromine, or any MAO inhibitor, in depressed patients unresponsive of either treatment given alone.

Disposition and urinary metabolic pattern of cabergoline, a potent dopaminergic agonist, in rat, monkey and man.

1. The disposition and urinary metabolic pattern of 14C-cabergoline was studied in rat, monkey and man after oral administration of the labelled drug. 2. In all species radioactivity was mainly excreted in faeces, with urinary excretion accounting for 11, 13 and 22% of the dose in rat, monkey and man, respectively. 3. After oral treatment, biliary excretion of radioactivity in rat accounted for 19% of the dose within 24 h. 4. Unchanged drug in 0-24-h urine samples of rat, monkey and man amounted to 20, 9 and 10% of urinary radioactivity, respectively. In the 24-72-h urine samples of all species the relative percentage of unchanged drug increased compared with that measured in the 0-24-h urine. 5. The main metabolite was the acid derivative (FCE 21589), which in 0-24-h urine samples of rat, monkey and man accounted for 30, 21 and 41% of urinary radioactivity, respectively. 6. Other metabolites identified in urine of all species resulted from hydrolysis of the urea moiety, the loss of the 3-dimethylaminopropyl group and the deallylation of the piperidine nitrogen.

Stereoselectivity of iododoxorubicin reduction in various animal species and humans.

1. The excretion of iododoxorubicin in urine as the 13-dihydro derivative, iododoxorubicinol, is much greater in man than in rat, dog, rabbit and monkey. Iododoxorubicinol epimers in urine from man and the animal species after i.v. administration of iododoxorubicin, were quantified by h.p.l.c. 2. (13R)-Iododoxorubicinol was not detectable in rat, dog and human urine and accounted for no more than 0.15% dose in urine of 1/3 rabbits and 3/3 monkeys. (13S)-Iododoxorubicinol in human urine amounted to 5.6% dose, whereas in rat only 0.01% dose and in monkey only 0.91% dose was found. 3. As for idarubicin, the in vivo reduction of iododoxorubicin is highly stereoselective, giving the (13S)-epimer almost exclusively. Erythrocyte ketone reductases may account for the higher formation of (13S)-iododoxorubicinol in man.

In vivo glucuronidation in rat and humans of 5,6-dihydro-7-(1H-imidazol-1-yl)-naphthalene-2-carboxylic acid, a selective inhibitor of thromboxane synthase.

The metabolites of 5,6-dihydro-7-(1H-imidazol-1-yl)-naphthalene-2-carboxylic acid, FCE 22178, a new thromboxane synthase inhibitor, were investigated in urine of rats and healthy volunteers after a single oral dose of 10 mg/kg and 400 mg, respectively, of the tritium-labeled drug. Cumulative urinary excretion of radioactivity after 4 days amounted to 64.6% and 91.0% of the dose in rat and humans, respectively. Urinary fractions of 0-24 hr, accounting for 61.8% and 79.5% of the dose, were analyzed by radio-HPLC with direct injection. Following incubation with beta-glucuronidase both in the presence and absence of saccharo-1,4-beta-lactone, a specific inhibitor of this enzyme, a metabolite was identified as a glucuronoconjugate of FCE 22178. The recovery of the glucuronide in the rat and man amounted to approximately 30% and almost 100% of urinary radioactivity, respectively. Control incubations showed a complete deglucuronidation in the case of rat urine compared with less than 10% in human urine. Addition of saccharo-1,4-beta-lactone abolished this phenomenon, suggesting the presence of an endogenous beta-glucuronidase in rat urine. Further identification of the only metabolite present in human urine by tandem MS analysis confirmed the structure of the acyl glucuronide of FCE 22178.

A study on the biological behavior of human brain tumors. Part I. Arachidonic acid metabolism and DNA content.

The study of proliferative characteristics and biochemical aspects seem to be of great importance in order to define brain neoplastic behavior. The purpose of this study is to verify the existence of any possible correlation between Arachidonic Acid (AA) metabolism and proliferative characteristics in 30 meningiomas and 30 neuroepithelial tumors. The most represented metabolite in neuroepithelial tumors is TxB2, while 6-Keto-PGF1 alpha is the lowest represented product. Unimodal DNA distribution was observed in 66% of neuroepithelial tumors and in 87% of meningiomas. Aneuploidy was more frequent in glioblastomas and anaplastic meningiomas as previously reported; AA overall synthesis capacity and profile were similar between unimodal and bimodal cases of neuroepithelial tumors. Total AA metabolite, as well as TxB2 and PGD2, synthesis capacity are significantly higher in cases with S-phase cell percentage greater than or equal to 3% than in cases with S-phase % less than 3%. Total production of AA metabolites via the cyclooxygenase pathway is significantly higher in meningiomas with bimodal DNA distribution than in cases with unimodal DNA content; when considering S-phase cell percentage, similarly to what observed in neuroepithelial tumors, meningiomas with S% greater than 3% shows a significantly higher overall synthesis capacity for AA. AA metabolism capacity well correlates with proliferative patterns in neuroepithelial tumors: the relationship depends preferentially on TxB2 and PGD2 synthesis capacity. In cases of meningiomas, the amount of AA metabolites seem to be related to DNA content and proliferative activity when anaplastic features are histologically demonstrated.

A study on the biological behavior of human brain tumors. Part II: Steroid receptors and arachidonic acid metabolism.

The significance of steroid receptors (SR) in human brain tumors is presently a field of intense investigation in order to clarify some aspects of the biological behavior of these neoplasms. We studied the relationship between the presence of steroid receptors and the production of metabolites of the arachidonic acid cascade which have been reported to have a role in the biological behavior of some human tumors. We found that some metabolites of arachidonic acid are produced in different amounts in brain tumors which either did or did not express some steroid receptors. In particular the PGE2 were higher in estrogen receptors (ER) positive meningiomas than in ER negative ones and 6-keto-PGF1 alpha, the stable metabolite of prostacyclin, is significantly higher in androgen receptors (AR) negative meningiomas than in AR positive ones. In neuroepithelial tumors the glucocorticoid receptors (GR) positive cases synthesized more TxB2 and less PGE2 than the GR negative ones. Our data seem to suggest that some correlations exist between the presence of some steroid receptors and arachidonic acid metabolite production.

Stereoselectivity of idarubicin reduction in various animal species and humans.

1. The (13S)-dihydro derivative of idarubicin, (13S)-idarubicinol, is the major urinary metabolite of idarubicin in humans. Idarubicinol epimers were quantified by h.p.l.c. in urine from rats, mice, rabbits, dogs and man after i.v. administration of idarubicin, and in man after oral dosing. The (13R)- and (13S)-epimers of idarubicinol were determined in rat bile. 2. After i.v. injection of idarubicin. (13R)-idarubicinol was not detectable in mice and rabbit urine and no more than 0.5% of the dose was present in the urine of other species. In man, the proportion of (13R)-idarubicinol in total idarubicinol was similar after i.v. (4.1%) and oral (3.8-5.0%) administration of idarubicin; the same applies to rat bile and urine. 3. Reduction of idarubicin in vivo is dependent upon ketone reductases, and proceeds more stereoselectively than that of most ketones giving rise to the (13S)-epimer almost exclusively. The high stereospecificity in idarubicin reduction might result from chiral induction due to the presence of asymmetric centres near to the carbonyl group in idarubicin.

Analysis of diethylstilbestrol, dienestrol and hexestrol in biological samples by immunoaffinity extraction and gas chromatography-negative-ion chemical ionization mass spectrometry.

A method has been developed for the detection of diethylstilbestrol, together with dienestrol and hexestrol, using extraction with a single immunoaffinity column containing antibodies raised against diethylstilbestrol, followed by gas chromatography-negative-ion chemical ionization mass spectrometry. Immunoaffinity columns were prepared by coupling immunoglobulin G fractions obtained from rabbit antisera with a Sepharose matrix. The immunizing agent was synthesized by introducing a carboxyl group into the diethylstilbestrol molecule and coupling this product to bovine serum albumin. The columns were used for immunoadsorption of diethylstilbestrol and other estrogens, after dilution of samples with phosphate buffer, and were eluted with acetone-water (95:5 v/v). A derivatization method suitable for gas chromatographic-mass spectrometric analysis of diethylstilbestrol and other estrogens was developed using pentafluorobenzyl bromide and ethanolic potassium hydroxide as reagents. The derivatives obtained were detectable at the sub-picogram level using gas chromatography with negative-ion chemical ionization mass spectrometry. Recoveries of cis- and trans-diethylstilbestrol, dienestrol and hexestrol from the immunoaffinity columns, determined after extraction from urine, plasma and buffer, ranged from 28 to 96%. The sensitivity for diethylstilbestrol in urine samples was ca. 10 ppt. The method was applied to the analysis of urine from calves given a single dose of 10 mg of diethylstilbestrol. Free and glucuronic acid conjugated diethylstilbestrol decreased with time, but their ratio was variable.

Prostaglandin and thromboxane synthesis by human intracranial tumors.

Prostaglandin (PG) and thromboxane (TX) production by homogenates of human intracranial tumors (33 gliomas, 32 meningiomas, six brain metastases) and "normal" brain (n = 26) from tumor-bearing patients was studied. PGF2 alpha, PGE2, PGD2, 6-keto-PGF1 alpha (the hydrolysis product of PGI2) and TXB2 (the hydrolysis product of TXA2) were determined by high-resolution gas chromatography-mass spectrometry after ex vivo metabolism of endogenous arachidonic acid. Prostanoid profiles (relative abundance of each metabolite) were different for gliomas and meningiomas, but similar for gliomas and their nontumoral counterpart, i.e., "normal" brain. Mean overall prostanoid production was significantly higher in gliomas (539 +/- 95) and meningiomas (523 +/- 69) than in "normal" brain (198 +/- 23). Prostanoid synthesis significantly increased with anaplastic grade (glioblastomas greater than anaplastic astrocytomas greater than slow-growing astrocytomas greater than "normal" brain), while profiles did not substantially change (TXB2 was the most and 6-keto-PGF1 alpha the least abundant product). Meningioma profiles showed no marked prevalence of any particular metabolite and no major differences between histological subgroups. All brain metastases from different carcinomas (n = 5) showed a prevalence of TXB2 and PGE2 and very low PGD2 synthesis.

Antiinflammatory action of salicylates: aspirin is not a prodrug for salicylate against rat carrageenin pleurisy.

A current hypothesis postulates that the antiinflammatory effect of aspirin (acetylsalicylic acid) is mediated by its metabolite salicylic acid through inhibition of PGE2 synthesis. We tested this hypothesis in rats with carrageenin-induced pleurisy. Aspirin or salicylate, given orally, reduced exudation and cell migration into the pleural cavity, aspirin being more potent than salicylate. The antiinflammatory effect of aspirin cannot be explained only in terms of salicylate formation. Doses of aspirin and salicylate that inhibit inflammation by 50% result in salicylate levels in the exudate of 70 +/- 12 and 323 +/- 17 micrograms/ml, respectively. At a significant antiinflammatory dose (100 mg/kg), salicylate did not reduce the prostaglandin and thromboxane content of the exudate. This indicates that inhibition of cyclooxygenase is not a likely mechanism for the antiinflammatory effect of salicylate. Salicylate only reduced the amount of 6-keto-PGF1 alpha in the exudate at higher doses (200 mg/kg), while aspirin at an equally antiinflammatory dose (50 mg/kg) reduced the content of 6-keto-PGF1 alpha, TXB2, PGD2 but not of PGE2 in the exudate. It therefore seems unlikely that an inhibition of PGE2 synthesis is the common mechanism by which aspirin and salicylate exert their antiinflammatory effects. These results do not supported the hypothesis that aspirin is a prodrug for salicylate but rather indicate that both compounds may exert their antiinflammatory effects partly by different mechanisms.

Prostaglandins in human brain tumors.

It has been recently observed that arachidonic acid (AA) metabolites may modulate many of the mechanisms involved in tumor growth and metastasis. In order to clarify the role played in human brain tumors, authors have determined AA metabolic profiles in 63 surgical specimen of human intracranial tumors (mostly neuroepithelial tumors and meningiomas). The five metabolites via the cyclooxygenase pathway (PGD2, PGE2, TxB2, PGF2a, 6-Keto-PGF1a) were measured by high resolution gas chromatography-mass spectrometry after "ex vivo" metabolism of endogenous AA by tumor homogenates. The overall synthesis capacity of AA metabolites widely varied among different oncotypes, and, except in two cases of dermoid cysts, was higher than in normal brain tissue. AA metabolism seems more active in neuroepithelial tumors with the highest grade of anaplasia; some changes in the percentage of each metabolite is evident when anaplastic features changed. Thromboxane B2 was the most represented and 6-Keto-PGF1a the less abundant metabolite. Meningiomas and neuroepithelial tumors showed different relative proportion of AA metabolites which have in some cases reported to positively or negatively affect tumor growth. In histological subgroups of meningiomas AA metabolites synthesis capacity did not show any statistical difference. In the six cases of brain metastasis there is a wide range of overall synthesis capacity, with predominant synthesis of thromboxane B2 and prostaglandin E2, while the percentage of prostaglandin D2, reported as antimetastatic, is very low.

Prostaglandin and thromboxane synthesis by M5076 ovarian reticulosarcoma during growth: effects of a thromboxane synthetase inhibitor.

The five stable metabolites [prostaglandin F2 alpha (PGF2 alpha), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha)] of arachidonic acid (AA) via the cyclooxygenase pathway were measured by high-resolution gas chromatography-mass spectrometry in M5076 ovarian reticulosarcoma (M5) homogenates at various times after tumor implantation (Days 15, 18, 21, and 24). Vegetating tumor showed an active AA overall metabolism, which significantly increased during tumor growth. Synthesis of selected products (TXB2, PGD2, and PGE2) increased markedly over time (up to 10.6, 3.5, and 0.9 micrograms/g, respectively). The overall metabolic profile was TXB2 much greater than PGD2 greater than PGF2 alpha greater than 6-keto-PGF1 alpha greater than PGE2 on Day 15 and TXB2 much greater than PGD2 much greater than PGF2 alpha greater than 6-keto-PGF1 alpha on Day 24. TXB2 was also by far the most abundant product of in vitro-cultured M5 cells. Chronic treatment of M5-bearing mice with dazmegrel (UK-38,485), a selective thromboxane synthetase inhibitor (100 mg/kg p.o. daily, from Day 7 to killing), resulted in incomplete TXB2 synthesis inhibition, AA metabolism diversion toward the other prostaglandins, and no effects of tumor growth and metastasis. More frequent dazmegrel treatment (100 mg/kg p.o. every 8 h from Day 1 to killing) resulted in complete TXB2 synthetase inhibition, AA metabolism diversion, and increased tumor growth and metastasis. These data do not support the hypothesis of thromboxane synthetase inhibitors reducing tumor growth. However, since TXB2 suppression was accompanied by the production of other products possibly interfering in tumor growth, no conclusions on the effective role of TXA2 in malignancy can be drawn.

Arachidonic acid metabolic profiles in human meningiomas and gliomas.

We determined arachidonic acid (AA) cyclooxygenase metabolic profiles in specimens of human intracranial tumors (gliomas and meningiomas) and, when available, normal brain tissue. Samples were collected at surgery and immediately frozen in liquid nitrogen. The five stable metabolites of AA (PGE2, PGD2, PGF2 alpha, 6-keto-PGF1 alpha and TXB2) were measured by high-resolution gas chromatography-mass spectrometry after ex vivo metabolism of endogenous AA by tissue homogenates. The absolute amounts of AA metabolites varied widely between samples, though meningiomas and gliomas showed characteristic profiles. Compared to the slow-growing benign meningiomas, the rapidly-growing infiltrating gliomas had higher synthesis of TXA2 (reported as a procancer metabolite) and lower synthesis of PGD2 and PGI2 (reported as anticancer metabolites). A higher overall synthesis capacity, preferentially toward TXA2, was found in glioblastomas than in non-pathological brain tissue.