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.

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.

Impairment of the metabolism of dipyrone in asymptomatic carriers of the hepatitis B virus.

BACKGROUND: The pharmacokinetics of a number of drugs has been shown to be impaired in patients with acute or chronic viral liver disease. OBJECTIVE: To examine the effect of the asymptomatic hepatitis B virus carrier state on the metabolism of dipyrone (INN, metamizole) as a model drug. METHODS: The pharmacokinetics of the metabolites of dipyrone-4-methylaminoantipyrine, 4-aminoantipyrine, 4-formylaminoantipyrine, and 4-acetylaminoantipyrine-after a 1.0 gm oral dose of dipyrone were evaluated in nine asymptomatic carriers of hepatitis B virus with normal liver function tests and nine healthy subjects. All subjects displayed the slow acetylator phenotype. RESULTS: The nonrenal (metabolic) clearance of 4-methylaminoantipyrine was significantly reduced (mean +/- SEM) (123.3 +/- 15.8 versus 182.9 +/- 15.1 ml.min-1, respectively; p < 0.02) in the carriers of hepatitis B virus compared with the healthy subjects, and the elimination half-life of this metabolite was significantly longer (3.69 +/- 0.35 versus 2.64 +/- 0.28 hours, respectively; p < 0.03). The formation clearances of 4-aminoantipyrine and 4-formylaminoantipyrine were significantly smaller in the carriers of hepatitis B virus compared with healthy subjects (33.8 +/- 6.2 versus 55.2 +/- 6.4 ml.min-1; p < 0.03, and 16.7 +/- 2.2 versus 34.2 +/- 4.2 ml.min-1; p < 0.002; respectively). However, the elimination half-life of 4-formylaminoantipyrine was found to be slightly shorter in the carriers of hepatitis B virus. No significant differences were noted between the groups in the pharmacokinetics of 4-acetylaminoantipyrine. CONCLUSION: The metabolism of dipyrone is impaired in asymptomatic carriers of hepatitis B virus. Clinically latent infection with hepatitis B virus seems to exert a differential effect on metabolism of the drug. Oxidative pathways to produce 4-aminoantipyrine and 4-formylaminoantipyrine were significantly affected, whereas acetylation remained intact. This study provided an additional example of the effect of a virus on the disposition of a drug.

Dipyrone metabolism in liver disease.

BACKGROUND AND OBJECTIVES: Dipyrone is an analgesic, antipyretic, and anti-inflammatory drug. After oral administration it is hydrolyzed to 4-methylaminoantipyrine and further metabolized to 4-aminoantipyrine, 4-formylaminoantipyrine, and 4-acetylaminoantipyrine. This study investigated the disposition of dipyrone metabolites in 12 hospitalized patients with cirrhosis (age, 25 to 65 years) and 27 healthy subjects of two age groups (young, 21 to 40 years; elderly, 73 to 90 years). METHODS: Subjects received 1 gm dipyrone orally, and blood samples were drawn and urine collected over 72 hours. Plasma and urine concentrations of the four metabolites were determined by HPLC. RESULTS: 4-Methylaminoantipyrine terminal elimination half-life (t1/2 beta) in patients with cirrhosis was prolonged compared with young and elderly subjects (mean +/- SEM, 10.6 +/- 0.6 versus 3.1 +/- 0.2 and 4.9 +/- 0.6 hours, p < 0.001), and the nonrenal clearance was reduced compared with the young subjects (1.069 +/- 0.243 versus 2.165 +/- 0.154 ml/min/kg, p < 0.005). 4-Formylaminoantipyrine was undetectable in two patients and in the remaining 10 patients, t1/2 was longer than in the young subjects (26.4 +/- 4.3 versus 10.8 +/- 0.7 hour, p < 0.01), whereas the elderly had intermediate values (18.1 +/- 2.8 hours). Clearance for production of 4-formylaminoantipyrine was reduced in the patients with cirrhosis than in the young and elderly subjects (0.109 +/- 0.024 versus 0.363 +/- 0.031 and 0.340 +/- 0.053 ml/min/kg, p < 0.001). The acetylation phenotype was determined to evaluate the pharmacokinetic parameters of 4-aminoantipyrine and 4-acetylaminoantipyrine. Prolongation of the 4-aminoantipyrine t1/2 and decrease in its clearance for production was found for the patients with cirrhosis, both slow and rapid acetylators, compared with the young and elderly subjects (p < 0.01). 4-Acetylaminoantipyrine t1/2 was also prolonged for patients with cirrhosis, slow and rapid acetylators, compared with the young subjects (p < 0.005). In the slow acetylators, clearance for production of 4-acetylaminoantipyrine did not differ between the patients with cirrhosis and the young subjects (p < 0.5); however, a difference was found for the rapid acetylators (p < 0.001). CONCLUSION: Our results show that the disposition of 4-methylaminoantipyrine, 4-aminoantipyrine, 4-formylaminoantipyrine, and 4-acetylaminoantipyrine is reduced by chronic liver disease after a single oral dose of dipyrone.

Validity of saliva samples for the estimation of dipyrone metabolites pharmacokinetics.

Plasma and saliva pharmacokinetics of dipyrone (CAS 5907-38-0) metabolites, 4-methylaminoantipyrine (MAA), 4-aminoantipyrine (AA), 4-formylaminoantipyrine (FAA) and 4-acetylaminoantipyrine (AAA), has been studied in 10 healthy volunteers, after oral administration of 1.0 g dipyrone, MAA, AA, FAA and AAA saliva concentrations correlated significantly with the respective plasma concentrations (r = 0.81, r = 0.62, r = 0.83 and r = 0.91, p < 0.001). MAA and AA concentrations in saliva were lower than in plasma while the FAA and AAA saliva concentrations were similar to the respective plasma concentrations. The saliva/plasma concentration ratios were highly dependent on sampling time. The elimination half-life of the final metabolites FAA and AAA can be equally evaluated from plasma and saliva data. For MAA, plasma and saliva t1/2 values were significantly correlated despite a substantial intra-subject difference. No correlation was found for AA plasma and saliva derived pharmacokinetic parameters. Similar to the plasma AAA/AA ratio, the saliva AAA/AA ratio in spot sample 6 h following oral dose might be proven to be a reliable discriminatory index for acetylation phenotyping.

Formation and excretion of dipyrone metabolites in man.

The formation and urinary excretion of the dipyrone metabolites, methylaminoantipyrine (MAA), aminoantipyrine (AA), formylaminoantipyrine (FAA) and acetylaminoantipyrine (AAA) were determined following administration of a single oral 1.0 g dose of dipyrone to 12 healthy volunteers. The AAA/AA plasma ratio showed that 3 subjects were slow and 9 were rapid acetylators. Pharmacokinetic parameters were determined separately for each group. A good correlation was found between the plasma and urine AAA/AA ratios. The renal clearance of the four metabolites was similar for both phenotypes. A significant difference in the rate of formation of dipyrone metabolites was found for AA, 0.25 (slow) vs 0.1 ml.min-1.kg-1 (rapid), and for AAA 0.75 (slow) vs 7.53 ml.min-1.kg-1 (rapid). There were comparable differences between slow and rapid acetylators in the AUC and the urinary excretion extrapolated to infinity for AA and AAA. The present results show that the kinetics of dipyrone metabolites in plasma and urine can provide a useful measure of the activity of the enzymes involved in their production.

Cyclosporine blood concentrations determined by different assay methods in heart transplant patients.

Cyclosporine (CsA) through blood concentrations were determined by polyclonal nonspecific radioimmunoassay (RIA) (Sandoz), monoclonal specific and nonspecific RIA (Sandimmun, Sandoz), monoclonal specific and polyclonal nonspecific RIA, (Cyclo-Trac, INCSTAR) and fluorescence polarization immunoassay (TDx, Abbott), at multiple points in time, in two patients receiving CsA for immunosuppression after heart transplantation. Results obtained by the different nonspecific methods have a correlation (r) from 0.76 to 0.94. Concentrations determined by Sandimmun nonspecific RIA, Cyclo-Trac nonspecific RIA and TDx were consistently higher than those by Sandoz nonspecific RIA, owing to different cross-reactivity with CsA metabolites, giving ratios of 1:8, 1:4, and 1:6, respectively. In the first patient, the ratios between nonspecific and specific results were higher during days 1-20 than later on, which coincides with the high serum bilirubin level observed (r = 0.72, n = 31). This observation was not made in the second patient, whose liver function was within normal limits. Because CsA and its metabolites are eliminated primarily in the bile, the high values obtained with the nonspecific assay indicate that CsA metabolites accumulate in blood when liver function is impaired.

Effect of age on the pharmacokinetics of dipyrone.

The pharmacokinetics of the dipyrone metabolite, 4-methylaminoantipyrine (MAA) was evaluated, following the administration of a single oral dose of dipyrone 1.0 g to 12 young (21-30 years) and 9 elderly (73-90 years) healthy volunteers. Maximal concentration, time to peak and absorption rate of MAA were similar for both groups. The elimination half-life was 2.6 (0.2) h for the young and 4.5 (0.5) h for the elderly subjects. Total clearance of MAA, corrected for lean body mass (LBM), was lower in the elderly than in the young 2.65 vs 3.97 ml.min-1.kg-1 LBM. There was no differences between the groups in the apparent volume of distribution. A good correlation was found between the total body clearance of MAA and the creatinine clearance, which was also reduced in the elderly (r = 0.61).

Influence of food on the pharmacokinetics of dipyrone.

Twelve healthy volunteers were given a single oral dose of dipyrone 1 g, once while fasting and once after a standard breakfast. Plasma levels of the active dipyrone metabolite-Methylaminoantipyrine (MAA) were measured and the calculated pharmacokinetic parameters were compared. Taking dipyrone with food resulted in a small delay in the mean time to peak from 1.5 h to 1.9 h (p less than 0.01). However, there was no significant difference in AUC, Cmax or K(elim) between fasting and nonfasting conditions. The rate of absorption, expressed as the mean K(abs), was somewhat slower in the nonfasting state, but not significantly so. It is suggested that dipyrone may be taken regardless of the times of eating.

Codeine-induced mast cell degranulation in human skin: effect of calcium channel blockers.

Codeine and other opiates can induce immediate type wheal and flare skin reactions. Calcium channel blockers including nifedipine have been shown to inhibit mast cell degranulation in different systems. The oral administration of nifedipine (10 mg) did not affect the size of codeine-induced skin reactions in ten normal volunteers. Mean wheal over flare sizes were 11.7 mm/29.2 mm before nifedipine and 11.5 mm/31.0 mm at peak nifedipine blood levels. Similar observations were made when codeine was injected locally with or without 20 micrograms nifedipine (12.1/29.2 mm and 13.2/29.2 mm, respectively). These data suggest that codeine-induced mast cell degranulation may be mediated by a calcium-independent mechanism. Alternatively, mast cells in the human skin may differ in their reactions to secretagogues when compared with basophils and mast cells from other human tissues or other species.

Excretion of dipyrone metabolites in human breast milk.

Breast milk and plasma levels of dipyrone metabolites in 8 mothers given a single oral dose of the drug were determined by HPLC. Four metabolites were demonstrated by the analytical method: 4-methylaminoantipyrine (MAA), 4-aminoantipyrine (AA), 4-formylaminoantipyrine (FAA) and 4-acetylaminoantipyrine (AAA). A good correlation was found between the plasma and milk concentrations of the metabolites. The mean (+/- SD) milk to plasma concentration ratios were: MAA = 1.37 +/- 0.28, AA = 1.15 +/- 0.40, FAA = 1.03 +/- 0.09, AAA = 0.97 +/- 0.24. The disposition pattern of the dipyrone metabolites in milk was studied in two mothers. None of the metabolites was detectable 48 h after drug administration.

Pharmacokinetic studies of nifedipine and digoxin co-administration.

We have studied the possible interactions between nifedipine and digoxin in 8 healthy subjects in two ways: A. The effect of digoxin (0.25 mg, tablet q.d. for 8 days) on the pharmacokinetics of nifedipine following single-dose (10 mg capsule) administration. Mean values for peak concentration, area under the serum concentration time curve (AUC), total serum clearance and the half-life of elimination of nifedipine did not differ before and concomitantly with digoxin administration. B. The effect of nifedipine (30 mg t.i.d.p.o. for 6 days) on the pharmacokinetics of digoxin following single dose (0.5 mg i.v.) administration. No significant differences were found between the mean values of the half-life of the alpha and beta phases, the AUC and the apparent volume of distribution of digoxin before and concomitantly with nifedipine administration. However, during the later period, the mean cumulative 96 h urinary excretion of digoxin increased by 18% (p less than 0.05) and the renal clearance of digoxin by 26% (p less than 0.05). No change was found, however, in the total plasma clearance of digoxin.

Plasma protein binding of dipyrone metabolites in man.

Four metabolites of dipyrone, 4-methylaminoantipyrine (MAA), 4-aminoantipyrine (AA), 4-formylaminoantipyrine (FAA) and 4-acetylaminoantipyrine (AAA) can be identified in human plasma after its oral administration. The plasma protein binding of the metabolites in samples from 20 healthy volunteers was determined by ultrafiltration. None of the metabolites were found to be extensively bound to plasma proteins. The binding of MAA and AA was relatively higher than of FAA and AAA, as expected from their chemical structure. The mean percentage plasma protein binding was 57.6% for MAA, 47.9 for AA, 17.8 for FAA and 14.2% for AAA. The correlation between the unbound concentration in plasma and the total concentrations of MAA, AA, FAA and AAA was linear. No association was evident between the total protein plasma concentration and the extent of binding. The possible therapeutic implications related to protein binding of several analgesic and non-steroidal anti-inflammatory drugs are discussed.

Relationship between caffeine concentrations in plasma and saliva.

Caffeine concentrations in plasma and saliva were measured by HPLC in 12 healthy subjects after a single oral dose of 250 to 350 mg. There was a linear relationship between caffeine concentrations in the two fluids. Mean (+/- SE) saliva: total plasma concentration ratio was 0.79 +/- 0.02, while the ratio of the free (non-protein bound):total concentration of drug in plasma was 0.59 +/- 0.01. We postulate that the higher saliva:total plasma ratio as compared to the plasma free: total ratio is a result of pH partitioning. The mean elimination t 1/2 estimated from plasma and saliva concentration-time curves were much the same (5.7 +/- 0.7 and 5.9 +/- 0.8 hr). Values for total body clearance and apparent volume of distribution obtained from saliva data were higher than values derived from plasma concentrations. These differences could be corrected by multiplying the saliva-derived parameters by the saliva: total plasma concentration ratio. We conclude that saliva sampling could serve as a useful technique for therapeutic drug monitoring as well as for research of caffeine kinetics when many samples are required.

Bioavailability of nifedipine: a comparison between two preparations.

In a random cross-over study, eight healthy volunteers received single 10 mg doses of either nifedipine capsule (Adalat, Bayer) or nifedipine tablets (Taro) after an overnight fast. The areas under the serum concentration time curves were not significantly different (AUC0----infinity 319.8 +/- 28.0 (SEM) ng ml-1 h-1 for capsules, 260.8 +/- 15.3 ng ml-1 h-1 for tablets). The peak serum levels and the time of their occurrence were 162.4 +/- 23.4 ng ml-1 at 30 min for capsules and 43.0 +/- 3.0 ng ml-1 at 1-2 h for tablets, indicating that the absorption of nifedipine from the capsule is faster than from the tablet form. Clinical symptoms of vasodilation corresponded with the nifedipine peak levels. We conclude that although the bioavailability in general of the two preparations is similar, the therapeutic equivalence may differ. Depending on the therapeutic indication each preparation may have its merits.

Plasma kinetics of dipyrone metabolites in rapid and slow acetylators.

The pharmacokinetics of the dipyrone metabolites 4-methylaminoantipyrine (MAA), 4-aminoantipyrine (AA), 4-formylaminoantipyrine (FAA) and 4-acetylaminoantipyrine (AAA) were evaluated following the administration of a single oral 1.0 g dose of dipyrone to 23 healthy volunteers. Twelve were slow and 11 were rapid acetylators as previously determined by dapsone phenotyping. For MAA and FAA the mean peak plasma concentrations were 10.5 +/- 2.8 micrograms/ml and 2.1 +/- 0.8 micrograms/ml and the half-lives were 3.3 +/- 1.0 and 10.1 +/- 1.8 h, respectively. No significant difference was found between rapid and slow acetylators in MAA and FAA kinetics. For AA, the mean peak plasma concentrations were 2.7 +/- 0.6 and 1.6 +/- 0.7 micrograms/ml (p less than 0.01), the peak times 6.7 +/- 2.1 and 3.1 +/- 1.1 h (p less than 0.01) and the half-lives were 5.5 +/- 1.0 and 3.8 +/- 1.2 h in slow and rapid acetylators, respectively. For AAA, the mean peak plasma concentrations were 1.6 +/- 0.4 and 4.4 +/- 1.1 micrograms/ml (p less than 0.01) and the peak time 16.1 +/- 5.1 and 10.0 +/- 2.6 h (p less than 0.01) in slow and rapid acetylators, respectively. There was no difference in the elimination half-life between the two groups (10.6 +/- 2.2 h). Thus, it has been demonstrated that the AAA/AA ratio is an indicator of the acetylation phenotype, as it is closely correlated with that determined by dapsone (r = 0.895, p less than 0.0005).

Gas-liquid chromatographic determination of bupivacaine and lidocaine in plasma.

A modified gas-liquid chromatographic method for determining plasma concentrations of bupivacaine and lidocaine is described, with cyclizine as an internal standard. The extraction procedure requires no solvent evaporation, thus overcoming the problem of drug volatility. Concentrations as low as 0.1 mg/liter can be determined. The plasma sample is made alkaline and extracted into n-hexane, re-extracted into a small volume of an aqueous acid phase, and finally extracted into 50 microliter of methylene chloride after alkalinization. The final extract is assayed by gas chromatography on a 5% OV-17 column. The extraction scheme of the present method eliminates interferences by endogenous plasma constituents.