Effect of cimetidine on the pharmacokinetics of the metabolites of metamizol.

Metamizol (dipyrone) is hydrolyzed in the gastrointestinal tract to the pharmacologically active metabolite 4-methyl-amino-antipyrine (4-MAA), which is transformed by both, oxidation to 4-formyl-amino-antipyrine (4-FAA) and demethylation to 4-amino-antipyrine (4-AA). 4-AA is acetylated to 4-acetyl-amino-antipyrine (4-AcAA). The aim of the present study was to investigate whether cimetidine will alter the pharmacokinetics of the metabolites of metamizol due to cimetidine-induced inhibition of the metabolic transformation of 4-MAA. The study was carried out in 12 patients with duodenal ulcer treated with cimetidine 1,000 mg daily over 20 days. A single oral dose of metamizol 1,500 mg was administered 2 days prior to commencement of cimetidine therapy to all patients. Two further doses of 750 and 1,500 mg of metamizol were given in a randomized order on days 8 and 13 during cimetidine treatment. Blood samples for determination of metamizol metabolites were drown over 48 hours post dose. Drug assays for metamizol metabolites and cimetidine were performed using HPLC methods. The patients were phenotyped for CYP2D6 and acetylation polymorphism. The results revealed that cimetidine interacted with 4-MAA by increasing the systemic availability, prolonging the elimination half-life and decreasing the systemic clearance of 4-MAA, whereas the renal clearances of 4-MAA remained unchanged. Consistent with cimetidine-induced changes in the oxidation of 4-MAA to 4-FAA, as well as in the demethylation of 4-MAA to 4-AA, were the decreased rates of production and the lower maximum concentrations of 4-FAA and 4-AA when metamizol was administered during cimetidine treatment (p < 0.05). No correlation was found between the decrease in the production rates of 4-FAA induced by cimetidine and the hydroxylation abilities of the patients, this suggesting that CYP2D6 is not involved in the metabolism of 4-MAA to 4-FAA. The acetylation of 4-AA to 4-AcAA was not affected by cimetidine. Cimetidine produced an increase not proportional to the dose in the systemic availability only of 4-MAA, whereas the kinetics of the other metabolites changed proportionally to the increasing dose of metamizol.

Genetic factors and risk of agranulocytosis from metamizol.

The role of genetic factors in the pathogenesis of agranulocytosis was investigated in agranulocytosis patients by phenotyping for N-acetyltransferase and glucose-6-phosphate polymorphism; by typing for gene products of the major histocompatability complex, ABO- and RH-blood groups, and haemoglobins; and by performing cytogenetic analysis of chromosome aberrations. Nine persons were identified as agranulocytosis cases in the period from 1982 to 1987 among the population of Sofia. They were contacted again 10 years after recovery from the disease. Five of them were associated with metamizol (dipyrone) use. The results obtained revealed significant differences between the agranulocytosis patients and the healthy population in the human lymphocyte antigen (HLA) allele frequencies, and in the degree and the frequency of chromosome aberrations. A higher frequency of the HLA24 antigen (relative risk 13.60, p = 0.05) and a lower frequency of the DQA1*0501 allele were evident for the ex-agranulocytosis patients as compared to the controls (11% versus 57% respectively, p = 0.05). In the patients exposed to metamizol, an A24-B7 haplotype was found with a frequency higher than that in the non-exposed patients and the reference group (p < 0.05). The HLA-DQwl antigen and metamizol-related agranulocytosis were evidently associated in all cases (5/5;100%) in contrast to the patients not exposed to metamizol and the controls. The HL-A2 antigen was absent in four of the five metamizol-associated agranulocytosis cases (20%), while in the control group it was present in 56%. The degree of structural rearrangements (0.62 +/- 0.2%) and the frequency of chromosome breakages (7.75 +/- 0.68%) in agranulocytosis patients were higher than those in the healthy population (0.3 +/- 0.12%, p < 0.05 and 1.42 +/- 0.27%, p < 0.01, respectively). The abnormalities affected predominantly chromosomes 1(1p13), 2(2p12) and 5(5p12). No differences were found between the agranulocytosis patients and the healthy population when considering the haemoglobin subtypes, ABO-and RH-blood groups, glucose-6-phosphate dehydrogenase activity and the rates of slow and rapid acetylators.

Lack of interaction between zidovudine and 4-methyl-amino-antipyrine, the active metabolite of metamizole, in human liver in vitro.

Zidovudine (AZT) is eliminated by extensive metabolism to an ether glucuronide (GAZT). The nonnarcotic analgesic metamizole (dipyrone) is a typical polydrug, the active metabolite being 4-methyl-amino-antipyrine (4-MAA). About 20% of 4-MAA is excreted in the form of glucuronide in the urine. The aim of this study was to investigate whether 4-MAA inhibits the glucuronidation of AZT, by comparing the GAZT formed in the presence and absence of 4-MAA in the microsomal fractions. Microsomal fractions were obtained from 6 human livers. AZT and 4-MAA were added in concentrations of 1 mmole, corresponding to the therapeutically relevant plasma concentrations of both drugs. Incubation time was 20 min. Concentrations of GAZT were measured using reverse-phase HPLC (high performance liquid chromatography). The mean value of GAZT formed in the microsomal samples without the addition of 4-MAA was 1.87 +/- 0.74 pmole/mg protein. In the presence of 4-MAA, the concentrations averaged 1.77 +/- 0.77 pmole/mg protein, and did not differ significantly from those measured without 4-MAA. In conclusion, the glucuronidation of AZT is not inhibited by 4-MAA, the main active metabolite of metamizole. From the in vitro findings it is predicted that concomitant metamizole administration may fail to enhance by metabolic interference the AZT concentrations under therapy.

Comparative bioavailability of two oral metamizole formulations. Influence of the acetylation phenotype.

The bioavailability of the four metabolites of metamizole (CAS 68-89-3), 4-methyl-amino-antipyrine (4-MAA), 4-formyl-amino-antipyrine (4-FAA), 4-amino-antipyrine (4-AA) and 4-acetyl-amino-antipyrine (4-AcAA) was compared after oral administration of a test (Analgin) and a reference formulation, both containing 1 g of metamizole. The study was conducted in 12 healthy volunteers according to an open, randomized, cross-over design. The geometric mean of the area under the serum concentration-time curves (AUC) of 4-MAA for the test formulation was 87.61 (57.58-133.30) micrograms.h/ml and was similar to that for the reference formulation (86.83; 53.86-139.92 micrograms.h/ml). No statistically significant differences between test and reference formulation were found with respect to the rate of absorption (Cmax, tmax, 100 Cmax/AUC) of 4-MAA. For 4-FAA, 4-AA and 4-AcAA, the 90% confidence intervals of the bioavailability parameters lay also within the bioequivalence ranges. Four of the subjects were rapid and eight were slow acetylators. No differences were found between slow and rapid acetylators in the bioavailability of 4-MAA, the pharmacologically active metabolite of metamizole.

The distribution of ciprofloxacin and its metabolites in human plasma, pulmonary and bronchial tissues.

The disposition of ciprofloxacin and its pharmacologically active metabolites (sulfociprofloxacin, oxociprofloxacin, and desethylenciprofloxacin) in plasma, lung and bronchial tissues was studied in 24 patients undergoing a partial or total resection of the lung. The patients were divided into four groups, a control group and groups in which ciprofloxacin (200 mg) was given i.v. 1, 2 and 3 h before surgery. The concentrations of ciprofloxacin and its metabolites were determined by high performance liquid chromatography (HPLC). Ciprofloxacin concentrations in lung tissue were four times and in bronchial tissue twice those in plasma (p less than 0.01). The individual tissue concentrations of ciprofloxacin correlated with the individual plasma concentrations (r = 0.95 for lung; r = 0.94 for bronchi; p less than 0.001). Metabolite concentrations in both tissues and plasma were 10- to 100-fold lower than the concentrations of ciprofloxacin. These data suggest that the concentrations of the parent compound are essential for the therapeutic efficacy of ciprofloxacin.

Pharmacokinetics and biliary concentrations of fleroxacin in cholecystectomized patients.

Patients with biliary tract infections received 800 mg of fleroxacin orally once daily on five consecutive days; cholecystectomy was on day 3. Starting on the day when dose 5 was administered, serial blood and T-drain bile samples were taken for 72 h and urine was collected for 96 h. The mean (+/- the standard deviation) peak concentration in plasma was 8.2 +/- 4.0 mg/liter at 8.3 h. The harmonic mean elimination half-life was 10.5 h, which is comparable to that reported for healthy volunteers. This increase resulted from reduced renal clearance (mean [+/- standard deviation], 38 +/- 22 ml/min), as the volume of distribution in the patients (1.4 +/- 0.7 liter/kg) did not differ from that reported for healthy subjects. Maximum concentrations in T-drain bile were high (median, 22.1 mg/liter) and exceeded those measured in plasma by a factor of 2 to 3; the individual ratios of the area under the curve for bile divided by that for plasma ranged from 1.3 to 9.9. As observed in healthy volunteers, the major pathway for elimination of fleroxacin was via the kidneys. The fraction of dose 5 eliminated in the 0- to 24-h urine was reduced, however, and the fraction of the dose in the urine as the N-demethyl and N-oxide metabolites was elevated. At the dose regimen used in this study, the MICs for most pathogens that cause biliary tract infections were surpassed in plasma and bile for more than 24 h.

Dose adjustment of nifedipine in hypertensive patients.

Ten patients with essential hypertension (WHO grade I-II) were treated in an open dose-adjustment study with the standard regimen of slow-release nifedipine 20 mg b.d. for 2 weeks and with an individualized dose for 6 weeks. The optimum dose, defined as that producing a pre-dose diastolic blood pressure (dBP) of 90 mm Hg at steady state, was determined from the individual concentration-effect relationship after a test-dose of 20 mg. On standard therapy, the reduction in pre-dose dBP was inadequate in 4 patients and it was excessive in 1 patient. After 2 weeks of individualized treatment, the required pre-dose antihypertensive effect was obtained in all patients. The individual doses required were 10 mg b.d., 10 mg t.d.s. 20 mg b.d., 20 mg t.d.s. and 20 mg q.d.s. One patient dropped out of the study because of side effects. Loss of the antihypertensive effect was observed in one patient after 6 weeks of treatment. On the optimized dose, the average value of the pre- and 2 h post-dose steady state nifedipine concentrations (27.6 micrograms/l) compared well with model-derived optimum concentrations (28.6 microliters/l) (r = 0.9210). The results show that the dose of nifedipine can be accurately predicted using the individual concentration-effect relationship after a single dose.

Pharmacokinetics of metamizol metabolites in healthy subjects after a single oral dose of metamizol sodium.

The linearity of the pharmacokinetics of the metamizol metabolites 4-methyl-amino-antipyrine (4-MAA), 4-amino-antipyrine (4-AA), 4-formyl-aminoantipyrine (4-FAA), and 4-acetyl-amino-antipyrine (4-AcAA) has been studied after administration to 15 healthy male volunteers of single oral doses of 750, 1500, and 3000 mg metamizol. The trial was open, randomized, and cross-over, with a one-week interval between dosing days. Metabolite concentrations in serum and urine were measured using reverse-phase HPLC. The mean Cmax of 4-MAA increased linearly with dose whereas its AUC was not proportional to dose after administration of 1500 and 3000 mg. With 4-AA, the increase in mean Cmax was linear, but the increase in AUC was not. The increases in mean Cmax and AUC for 4-FAA after doses of 1500 and 3000 mg were not proportional to the dose. The increases in mean Cmax and AUC for 4-AcAA were roughly proportional to the increase in dose. There were no significant differences in renal clearance between doses for any of the four metabolites. The observed non-linearities reflect the saturability of metabolic pathways. However, although they were statistically significant, the deviations from linearity were marginal and should not be of clinical relevance to the analgesic efficacy of metamizol in the dose range tested.

[The bioequivalence of two nifedipine fluid capsules]. / Zur Bioäquivalenz von zwei Nifedipin-Flüssigkapseln.

Bioequivalence of Two Nifedipine Liquid Capsules Plasma concentration-time profiles of nifedipine were determined in an open, randomised cross-over study on 12 healthy volunteers after application of 10 mg nifedipine as two different soft gelatin capsule preparations. In vitro dissolution tests showed a significant difference between the reference preparation (R) and the generic preparation (P). Maximal nifedipine plasma concentrations (Cmax) measured at tmax (0.6 h, median) for P averaged 87.5 +/- 32.7 micrograms/l, corresponding values for R were 95.4 +/- 41.1 micrograms/l and 0.46 h. Differences in Cmax and tmax values were not statistically significant. Mean areas under the curves AUC(0-10 h) were 128.7 +/- 59.9 micrograms.h/h after p and 123.3 +/- 49.3 micrograms.h/l after R (n.s.). 95% confidence intervals for indices of bioavailability based on AUC and Cmax overlapped, indicating that the two preparations are bioequivalent.

Effects of beta-adrenergic agents on the regional cerebral blood flow in cortex and thalamus of the cat.

The effects of the beta-adrenergic agents isoprenaline, terbutaline, l,d-propranolol, acebutolol, as well as d-propranolol, on the regional cerebral blood flow (rCBF) in cortex and thalamus and arterial blood pressure (ABP) were investigated following i.v. administration. The experiments were performed in 64 cats anaesthetized with ether and chloralose. The rCBF was measured using the thermistor thermoclearance technique. Isoprenaline, as well as terbutaline (1, 3, 5 micrograms/kg) decreased the cortical rCBF and the ABP (p less than .05). Both adrenergic agonists increased the thalamic rCBF despite the decrease in ABP (p less than .05). L,d-propranolol (1 mg/kg) abolished the effects of isoprenaline and terbutaline on thalamic rCBF. Acebutolol (0.6 mg/kg) or d-propranolol (0.5 mg/kg) did not alter isoprenaline- and terbutaline-induced effects on rCBF in thalamus. L,d-propranolol decreased the thalamic rCBF, whereas d-propranolol increased the rCBF in thalamus (p less than .05). Acebutolol did not change the thalamic rCBF significantly. The results obtained indicate that beta-adrenergic agents have heterogeneous effects on rCBF in cortex and thalamus. Their effects on thalamic rCBF seem to be accomplished by beta 2-adrenoceptor stimulation.

Autoregulation of the regional cortical and thalamic cerebral blood flow in cats.

The autoregulation of regional cerebral blood flow (rCBF) in cortex and thalamus upon an increase in systemic arterial blood pressure (ABP) was investigated in 27 cats before and after pretreatment with phentolamine (1 mg/kg, i.v.), propranolol (1 mg/kg, i.v.) or acebutolol (1.2 mg/kg, i.v.). The animals were anaesthetized with ether and chloralose. rCBF was measured by thermistor thermoclearance technique. ABP elevation was produced by angiotensin i.v. infusion. rCBF autoregulation was evaluated using different criteria--limits and indices of autoregulation. The data obtained indicate that thalamic rCBF is more resistant to ABP elevation than cortical rCBF. Phentolamine did not change rCBF autoregulation in cortex and thalamus. Propranolol did not change the cortical but increased the thalamic rCBF resistance to ABP elevation. Acebutolol did not influence rCBF autoregulation in thalamus. The results suggest that different mechanisms are involved in rCBF autoregulation in cortex and thalamus. They can be selectively influenced by pharmacological agents.

Liver insufficiency as a factor modifying the pharmacokinetic characteristic of the preparation nabumetone.

The effectiveness of the nonsteroidal anti-inflammatory agent nabumetone is related to the formation of an active metabolite: 6-methoxy-2-naphthylacetic acid. The plasma concentrations of nabumetone and its active metabolite, after administration of 1,000 mg single dose p.o., are followed at 0, 0.5, 1, 2, 4, 6, 8, 12, 24, 30 and 48 h in 6 patients with laboratory evidence for functional liver insufficiency caused by liver cirrhosis, confirmed by biopsy. In the patients with liver insufficiency the mean values of Cmax and AUC0-24 h for 6-methoxy-2-naphthylacetic acid were 26.75 +/- 8.45 mg/l and 623.64 +/- 161.8 mg X h/l respectively. They did not differ significantly from the values observed in healthy volunteers [v. Schrader et al. 1983]. The Tmax-value was prolonged to 8 h, compared to 4 h Tmax-value of the volunteers. There is a tendency towards a reduced bioavailability of 6-methoxy-2-naphthylacetic acid after nabumetone administration in patients with a more severely expressed pathologic impairment, compared to patients with slight morphologic changes of the liver parenchyma.