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PubMedDate not supplied

Dose-dependent pharmacokinetics of metabolites of dipyrone in saliva.

Metabolites of dipyrone have been determined in the saliva of 18 volunteers following the oral intake of 0.5 g, 1.0 g, 1.5 g, 2.0 g and 2.5 g dipyrone. High concentrations were measured for N-methyl-aminoantipyrine (MAA), the other analgetic active metabolite, 4-aminoantipyrine was found in minor quantities only. N-formyl-antipyrine was not present in the saliva of some volunteers after low doses but could be determined following the intake of doses from 1.5 g - 2.5 g in saliva of all volunteers. N-acetyl-antipyrine appears late in saliva, acetylation rates varied greatly interindividually. Concentrations of the metabolites in saliva mimic the respective non-protein bound fraction in plasma found by other authors.

Adult↗
PubMed1998

Cerebrospinal fluid and plasma concentrations of dipyrone metabolites after a single oral dose of dipyrone.

OBJECTIVE: Dipyrone is a veteran analgesic and antipyretic drug. After oral administration it is rapidly converted by hydrolysis to 4-methylaminoantipyrine (MAA), which is further metabolized to 4-formylaminoantipyrine (FAA), 4-aminoantipyrine (AA) and 4-acetylaminoantipyrine (AAA). It is still debated whether the site of dipyrone action is in the central nervous system or in the periphery. The purpose of this study was to assess whether dipyrone metabolites cross the blood-brain barrier (BBB) when administered systemically. METHODS: Twenty-eight patients undergoing diagnostic lumbar puncture (LP) were randomly assigned to receive two 0.5-g dipyrone tablets either 30 min, 1, 1.5, 2, 4, 6, 8 h or 12 h before the lumbar tap. A 5-ml blood sample was drawn concomitantly. RESULTS: All four metabolites were found in the cerebrospinal fluid (CSF). Their appearance in the CSF lagged but followed that found in the plasma. Mean CSF/plasma ratios were 0.40 (for samples taken between 0.5-2 h) and 0.83 (for samples taken between 4-12 h) for MAA, 0.62 for AA, 0.55 for FAA and 0.40 for AAA (for all samples). Significant correlation was found between plasma and CSF concentrations for MAA, AA, FAA and AAA. CONCLUSION: The concentration-time course of dipyrone metabolite CSF concentrations are in agreement with that of their plasma concentrations and the analgesic effect of dipyrone.

Administration, Oral↗
PubMed2001

Impairment of the metabolism of dipyrone in asymptomatic carriers of the hepatitis-B virus does not occur in rapid acetylators.

OBJECTIVE: We previously found that, compared with healthy subjects. asymptomatic hepatitis-B virus (HBV) carriers displaying slow acetylator phenotype demonstrate a significant prolongation of the elimination half-life of 4-methylaminoantipyrine (MAA) and a decrease in the clearance of formation of 4-aminoantipyrine (AA) and 4-formylaminoantipyrine (FAA). However, the formation of 4-acetylaminoantipyrine (AAA) was unchanged. The present study was designed to examine the effect of the asymptomatic HBV carrier state on the metabolism of dipyrone. as a model drug, in rapid acetylators. METHODS: The plasma and urine concentrations of the metabolites of dipyrone were measured in eight asymptomatic HBV carriers and eight healthy subjects who had normal liver function tests, all displaying the rapid acetylation phenotype and genotype, after the administration of a 1.0-g oral dose of dipyrone. RESULTS: The following pharmacokinetic parameters were evaluated: peak plasma concentration, time to peak plasma concentration, elimination rate constant, area under the plasma concentration-time curve (0-->infinity), amount excreted (0-->infinity), renal and non-renal clearances for MAA and the clearances of formation for AA, FAA and AAA. No significant differences were found between the two subject groups. CONCLUSION: The effect of hepatic viral carrier state on drug metabolism may vary according to metabolic pathways and genetic polymorphism.

Acetylation↗
PubMed1996

A comparison of methods for limited-sampling strategy design using data from a phase I trial of the anthrapyrazole DuP-941.

The pharmacokinetics of a drug in individual patients can be estimated using plasma samples collected at a limited number of time points. However, different methods for a limited-sampling strategy (LSS) design exist and the optimal method has not yet been defined. Plasma concentration data were available from 27 of 74 courses in a phase I study (dose range, 5-55 mg m-2) of the novel anthrapyrazole DuP-941. Three approaches to LSS development were compared. Firstly, forward stepwise regression (FSR) was used to derive equations to predict the DuP-941 area under the concentration-time curve (AUC) based on plasma concentrations measured at specified times. LSSs were developed using 14 randomly chosen data sets and were validated using the remaining 13 data sets. Secondly, "all subsets" regression (ASR) was used to develop LSSs. A jack-knife technique was also used to allow model development utilising 26 data sets and validation on the 27th data set. Thirdly, an LSS was developed using optimal sampling theory (OST), and the LSS was used in conjunction with a Bavesian algorithm. Selected sampling times for four-point LSSs were 10, 65, 185 and 485 min (FSR) and 10, 45, 200 and 480 min (OST). Ten candidate LSSs were developed using the ASR approach. ASR- and OST/Bayesian-derived four-point LSSs gave more precise (P < 0.05) estimates of AUC [mean absolute percentage of difference (MAD%) +/- SD: ASR, 6.4 +/- 3.7%; OST/Bayesian, 6.8 +/- 4.6%] than did FSR (MAD% = 15.1 +/- 9.9%). The OST/Bayesian approach is recommended because it allows estimation of all model parameters and is more flexible with regard to sample collection time and design variables.

Adult↗
PubMed1998

Identification of famprofazone ingestion.

After a traffic accident a 32-year-old man was suspected of having previously taken an illegal drug. An immunochemical screening procedure revealed positive results for amphetamines in both urine and blood samples. The preliminary test was confirmed by GC/MS and both amphetamine and methamphetamine were found in both body fluids. However, the man denied any use of drugs but claimed to have taken four tablets of Gewodin. One of the ingredients, famprofazone, undergoes metabolic conversion to amphetamine and methamphetamine. Using GC/ MS the ingestion of famprofazone was verified by identification of the unchanged parent compound in the urine sample.

Adult↗
PubMed1984

The beneficial effects of nafazatrom (BAYg6575) on experimental coronary thrombosis.

An in vivo model of coronary artery thrombosis in the conscious dog was used to evaluate the potential antithrombotic effect of nafazatrom (BAYg6575). A silver wire electrode was implanted in the left circumflex coronary artery (LCX) and was used at a later time to deliver a 50 uA anodal current for 24 hours to the intimal surface of the vessel. The resulting injury to the endothelium was accompanied by the adhesion, aggregation, and subsequent formation of an occlusive thrombus in the LCX of vehicle-treated dogs. Nafazatrom was given as an intravenous dose of 1 mg/kg for 48 hours, before anodal stimulation of the coronary artery was initiated, and was repeated every 6 hours during anodal stimulation for a total treatment period of 72 hours. As compared to vehicle-treated control dogs, the dogs treated with nafazatrom had smaller thrombi, preservation of coronary blood flow, a lesser degree of ischemic injury in the myocardial region subserved by the LCX, and less frequent premature ventricular complexes during the final 12 hours of the study period. Concomitant ex vivo platelet aggregation studies revealed significant inhibition of platelet aggregation in response to collagen and adenosine diphosphate in drug-treated dogs. The results of these investigations provide evidence that nafazatrom prevents in vivo development of occlusive coronary artery thrombi in response to disruption of the endothelial surface of the vessel.

Adenosine Diphosphate↗
PubMed1985

Lack of efficacy of nafazatrom, a novel anti-thrombotic compound, in patients with coronary artery disease.

Nafazatrom (Bay G 6575) is a novel antithrombotic compound, which acts by stimulation of prostacyclin as well as by inhibition of lipoxygenase enzymes. To determine its effects on exercise performance in coronary artery disease patients, a double-blind study was conducted. Twenty patients with coronary artery disease underwent an exercise stress test before and 2 hours after administration of placebo or nafazatrom (1.2 gm). Before the drug administration, there was evidence of enhanced platelet activity, as reflected by elevated resting plasma beta thromboglobulin and thromboxane B2 concentrations. Plasma 6-keto-PGF1 alpha levels were undetectable in most patients. All coagulation tests were in the normal range. None of these parameters changed with exercise. Administration of placebo or nafazatrom before the exercise stress test did not significantly influence any of the coagulation or platelet function parameters or plasma concentrations of thromboxane B2 and 6-keto-PGF1 alpha. This lack of effect was evident both at rest and upon exercise. Compared to placebo, nafazatrom did not significantly increase exercise tolerance time or exercise-induced symptoms. In conclusion, nafazatrom did not influence exercise performance in patients with coronary disease.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Effect of nafazatrom on platelet function and release: relationship to symptomatic episodes in patients with peripheral vascular disease.

We studied the effect of nafazatrom on plasma prostacyclin (PGI2) levels, platelet function, and thromboxane B2 (TxB2), and 12-hydroxy-eicosatetraenoic acid (12-HETE) production and clinical improvement in 12 patients with peripheral vascular disease (PVD) by means of a double-blind crossover trial of placebo, 800 or 1600 mg of nafazatrom four times daily for 1 week, with intervening 2-week washout periods. Plasma PGI2 levels were measured as 6-keto-PGF1 alpha by radioimmunoassay. Platelet function ex vivo was measured as collagen and adenosine diphosphate (ADP)-induced platelet aggregation, release of 12-HETE and thromboxane A2 (measured as TxB2), and was determined by high-pressure liquid chromatography (HPLC) and radioimmunoassay, respectively. The plasma 6-keto-PGF1 alpha levels were unaffected by nafazatrom treatment (p greater than 0.25). Nafazatrom treatment had no effect on TxB2 production, but significantly altered the production of the platelet 12-HETE (p less than 0.05). There was a significant association between the changes in 12-HETE production and clinical improvement. These results suggest that the mechanism of action of nafazatrom is in part related to the inhibition of platelet function via the lipoxygenase pathway, independent of PGI2 stimulation.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1988

Aminopyrine metabolism by multiple forms of cytochrome P-450 from rat liver microsomes: simultaneous quantitation of four aminopyrine metabolites by high-performance liquid chromatography.

Four aminopyrine metabolites generated by hepatic microsomes were simultaneously assayed by high-performance liquid chromatography. The metabolites were 4-monomethylaminoantipyrine (MAA), 4-aminoantipyrine (AA), 3-hydroxymethyl-2-methyl-4-dimethylamino-1-phenyl-3-pyrazoline-5-one (AM-OH), and one unidentified metabolite. MAA was the major metabolite generated by the microsomes; its formation was induced by phenobarbital but not by 3-methylcholanthrene. Female rats had lower N-demethylation activity of aminopyrine than male rats. The production of AA by microsomes was low. The formation of AM-OH was strongly induced by phenobarbital, but treatment with 3-methylcholanthrene reduced its formation. These differences in the microsomal aminopyrine monooxygenase activity are dependent on the relative amounts of the individual cytochrome P-450 isozymes. Therefore, we examined aminopyrine metabolism in a reconstituted system with purified cytochrome P-450s. P-450 UT-2 (P-450h) had high aminopyrine N-demethylation and hydroxylation activities, but P-450 F-2 (P-450i) had low N-demethylation activity and no hydroxylation activities, but P-450 F-2 (P-450i) had low N-demethylation activity and no hydroxylation activity. P-450 PB-4 (P-450b) and P-450 PB-5 (P-450e) had high aminopyrine hydroxylation activity and their N-demethylation activity also was high. The 3-methylcholanthrene-inducible forms P-450 MC-1 (P-450d) and MC-5 (P-450c) had aminopyrine N-demethylation activity but no hydroxylation activity. P-450 UT-4 (RLM2) is a unique form that produced a large amount of the unknown metabolite. P-450 UT-7 had the highest N-demethylation activity. Addition of cytochrome b5 to the reconstituted system enhanced the aminopyrine hydroxylation activities of P-450s UT-1, UT-2, PB-2, and PB-5. Also, the N-demethylation activities of P-450s UT-1, PB-1, PB-2, and MC-1 were increased by cytochrome b5. Metyrapone inhibited the catalytic activities of P-450s PB-4, PB-5, MC-1, and MC-5, and especially those of P-450s UT-4, and UT-7. The kinetics of the four major cytochrome P-450s (P-450 UT-2, UT-4, PB-4, and MC-5) for aminopyrine N-demethylation and hydroxylation activities were studied. P-450s PB-4 and UT-2 had similar Km values (0.50 and 0.62 mM, respectively) in aminopyrine N-demethylation activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Aminopyrine↗
PubMed1986

Effects of anthrapyrazole antineoplastic agents on lipid peroxidation.

The effects of three anthrapyrazoles and an aminoacridine derivative on doxorubicin- and iron-stimulated lipid peroxidation in rabbit hepatic microsomes have been characterized. Two anthrapyrazoles, CI-937 and CI-942, were potent inhibitors of lipid peroxidation with 15 microM drug inhibiting the rate of peroxidation 70 to 90%. In contrast CI-941 was relatively ineffective in inhibiting lipid peroxidation with only 35% inhibition occurring at 100 microM drug. CI-921, an aminoacridine derivative, diminished lipid peroxidation by 65% at 15 microM. All four drugs failed to decrease the rate of doxorubicin-stimulated NADPH oxidation at concentrations less than 50 microM, suggesting that inhibition of lipid peroxidation was not the result of diminished enzyme activity. CI-937 formed a 2:1 complex with ferric ion, KD = 47 microM, which was reversible with EDTA.

Amsacrine↗
PubMed1983

Manipulation of the local thromboxane and prostacyclin balance in vivo by the antithrombotic compounds dazoxiben, acetylsalicylic acid and nafazatrom.

We have developed an experimental model for the study of local prostaglandin production by platelets and the vessel wall following stimulation 'in vivo'. A nylon thread was inserted into the external jugular vein of rabbits; its presence did not induce an occluding thrombus. Thromboxane (TXB2) values in the blood, sampled through the facial vein, immediately distal to the stimulus, rose and remained high for at least 4 hr, while 6-keto prostaglandin (PG) F1 alpha levels, after a first increase, gradually returned to normal ('exhaustion' of the endothelial cells?). No changes were observed in the contralateral jugular vein without thread. After infusion via the femoral vein of 10 mg/kg dazoxiben, a thromboxane synthetase inhibitor, local TXB2 production was completely abolished, whereas 6-keto PGF1 alpha formation no longer returned to basal values, but tended to increase. This leads to the conclusion that upon inhibition of TXB2 formation endoperoxide metabolism is reoriented 'in vivo' towards prostacyclin, and this mainly at the site where platelets are activated. Injection of 100 mg/kg lysine acetylsalicylic acid resulted in complete inhibition of TXB2 and 6-keto PGF1 alpha formation, the latter, however, slowly recovering with time. The administration of nafazatrom to the animals did not influence the local TXB2 changes, but partially prevented the decline of 6-keto PGF1 alpha with time. The antithrombotic properties of this drug thus could be related to protection of the endothelial cells from 'exhaustion'.

Animals↗
PubMed1983

In vivo and in vitro effects of nafazatrom (Bay g 6575), an antithrombotic compound, on arachidonic acid metabolism in platelets and vascular tissue.

Nafazatrom, given acutely to male volunteers, had no effect on platelet aggregation, associated thromboxane B2 (TXB2) formation or the evaluated hormonal, renal and cardiovascular parameters. Only slight increases in plasma levels of 6-keto-PGF1 alpha and in platelet counts were observed. However, a marked influence of nafazatrom on arachidonic acid metabolism in certain in vitro systems was found. Prostaglandin synthesis by rabbit kidney cortex microsomes was significantly enhanced, PGI2 being stimulated the most. In normal human platelets arachidonic acid metabolism was not influenced significantly by nafazatrom which was taken up by the platelets in a dose-dependent manner. In contrast, in platelets with a high peroxide level probably due to depletion of reducing cofactors, 12-hydroperoxy-eicosatetraenoic acid was transformed to 12-hydroxy-eicosatetetraenoic acid by nafazatrom, while the formation of TXB2 was stimulated. These findings suggest that nafazatrom may act as a reducing cofactor for the hydroperoxidase involved in the cyclooxygenase- and lipoxygenase-pathways of arachidonic acid metabolism.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Inhibition of leukotriene B4 formation in human neutrophils after oral nafazatrom (Bay g 6575).

Three grams of nafazatrom (Bay g 6575), given orally to healthy male volunteers in a single dose, significantly reduce the formation of leukotriene B4 in polymorphonuclear leukocytes. LTB4 synthesis fell from 57.1 +/- 17.0 ng/10(7) PMNL, mean +/- S.D., in control to 34.3 +/- 14.4 ng/10(7) PMNL 3 hr after nafazatrom (2 P less than 0.001). In vitro, nafazatrom inhibited LTB4 formation in human PMNL in a dose dependent manner. At 1 microM nafazatrom LTB4 formation was reduced to 65% of the control value. Nafazatrom had no effect on the excretion of 2,3-dinor-6-keto-PGF1 alpha and 2,3-dinor-TXB2, the major urinary metabolites of endogenously synthesized PGI2 and TXA2, respectively. Serum levels of TXB2 in clotted whole blood also remained unchanged. The inhibitory effect of nafazatrom on leukotriene biosynthesis in human PMNL suggests a therapeutic potential of this drug in processes like allergy and chronic inflammation, where leukotrienes play a pathogenetic role.

Administration, Oral↗
PubMed1986

Leukocyte recruitment in the subcutaneous sponge implant model of acute inflammation in the rat is not mediated by leukotriene B1.

The subcutaneous sponge implant model of acute inflammation in the rat has been evaluated as a suitable test system for evaluating the potential anti-inflammatory efficacy of 5-lipoxygenase inhibitors. The inflammatory parameters measured were exudate volume and leukocyte recruitment. Specific radioimmunoassays were used to measure (1) 5-lipoxygenase (LPO) and cyclo-oxygenase (CO) activity in exudate leukocytes stimulated ex vivo with A23187, and (2) the LTB4 and PGE2 content of inflammatory exudate. The NSAIDs flurbiprofen and indomethacin inhibited cell recruitment, exudate volume and CO activity with ED50S of approximately 1 mg per kg p.o. but failed to inhibit LPO activity at 10 mg per kg p.o. Nafazatrom (Bayer 6575), quercetin and NDGA, which inhibit LPO activity in vitro, were inactive against all parameters when dosed at 100 mg per kg p.o. The "mixed inhibitors" BW755C and phenidone were approximately equipotent inhibitors of LPO activity but BW755C was 10 times more potent than phenidone against CO activity. BW755C was also greater than 10 times more potent at inhibiting cell recruitment and exudate volume than phenidone suggesting that the anti-inflammatory efficacy of the mixed inhibitors reflect their potency against CO rather than LPO activity. Time course studies demonstrated that the inhibitor effects of BW755C and phenidone on leukocyte recruitment reflected a reduction in the PGE2 but not the LTB4 content of the inflammatory exudate. Polyester sponges soaked in high concentrations of LTB4 caused only a modest (2-fold) increase in leukocyte recruitment whilst physiological levels were inactive. The results taken together suggest that CO products make a major contribution to leukocyte recruitment in this model whilst the LPO product LTB4 has little role. This model therefore is of little value for evaluating the anti-inflammatory efficacy of 5-lipoxygenase inhibitors. Moreover, the rat would appear to be unsuitable for evaluating the role of LTB4 in acute inflammation.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1987

The effect of the anthrapyrazole antitumour agent CI941 on rat liver microsome and cytochrome P-450 reductase mediated free radical processes. Inhibition of doxorubicin activation in vitro.

The anthrapyrazole CI941 is one of a new series of DNA complexing drugs which displays high level broad spectrum antitumour activity in mice. In view of the proposed role of drug free radical formation, superoxide generation and lipid peroxidation in anthracycline and anthraquinone induced toxicities, the redox biochemistry of CI941 has been investigated. Studies have been performed in vitro using rat liver microsomes and purified cytochrome P-450 reductase. In addition, the ability of CI941 to undergo chemical reduction has been examined. Pulse radiolysis of CI941 demonstrated that the drug can undergo chemical reduction with a one electron reduction potential of E1(7) = -538 +/- 10 mV. However, electron spin resonance (ESR) spectroscopy studies using either NADPH fortified microsomes or cytochrome P-450 reductase, failed to detect a drug free radical signal. Unlike doxorubicin, CI941 (150 microM) inhibited basal rate microsomal NADPH consumption by 45%. Furthermore, CI941 (50-200 microM) antagonised doxorubicin stimulated (1.8-fold) NADPH oxidation by over 50%. CI941 also antagonised the formation of a doxorubicin free radical ESR signal in a concentration dependent manner. CI941 induced minimal superoxide generation in the presence of either microsomes or cytochrome P-450 reductase and inhibited doxorubicin induced (50 microM) superoxide formation by up to 80% (50-200 microM CI941). Importantly, CI941 inhibits both basal rate and doxorubicin (100 microM) stimulated lipid peroxidation (52% inhibition at 5 microM CI941). These data suggest that CI941 is unlikely to induce free radical mediated tissue damage in vivo. On the contrary, CI941 may have a protective role if used in combination with doxorubicin.

Animals↗
PubMed1989

Some properties of an inhibitory cytochrome P-450 metabolic-intermediate complex existing in a spin-state equilibrium.

Incubation, in the presence of NADPH/O2, of the type II compound revenast with a partially solubilized, phenobarbital-induced rat liver microsomal cytochrome P-450 system results in the formation of a difference spectrum exhibiting a Soret band at 407 nm and a trough at 423 nm. Experiments with N2 and metyrapone suggest this spectral perturbation to originate from binding to the hemoprotein of a metabolic intermediate derived from the amine substrate. The percentage of pigment complexed can be assessed to be about 7%, with half-maximal complexation occurring at a revenast concentration of 125 microM. Adduct formation is inhibitory to the N-hydroxylation of 4-chloroaniline and N-demethylation of N,N-dimethylaniline; kinetic analysis suggests a competitive interaction at the catalytic site of the reactive revenast derivative with the tertiary arylamine. Inhibition of the two monooxygenation reactions is reversible, indicating weak heme bonding of the active intermediate. This behaviour differs from that of most other product adducts so far examined. The aberrant functional properties of the metabolic adduct appear to reflect complex molecular organization of this compound, as is also evidenced by the unique position of the Soret region absorption maximum at 407 nm; this spectral data hints at the presence of a mixture of high- and low-spin forms. Indeed, chemical reduction or oxidation of the product complex reveals the existence of a low-spin component hidden in the metabolic spectrum. Model studies suggest that the product adduct possibly arises from N-oxidation of the revenast molecule.

Aniline Compounds↗