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.

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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.Oral treatment of serious and resistant bacterial infections was considerably improved by introduction of fluorinated 4-quinolones during the past decade (18). These new antiinfective agents provided high in vitro activity against a broad spectrum of gram-positive and gram-negative bacteria, and their clinical efficacy was impressive (3,11,14,15).A relatively new addition to this group of antibiotics is fleroxacin. In healthy volunteers, fleroxacin was completely absorbed after oral administration (22). The peak concentration in plasma averaged 4.36 mg/liter after a 400-mg dose (n = 12, standard deviation [SD] = 1.15), which surpassed for more than 24 h the MIC for 90% of strains of a broad spectrum of fleroxacin-susceptible pathogens. Within 2 to 3 days, 50 to 60% of the dose was recovered from the urine as unchanged drug; in addition, 10 to 20% was renally excreted as the N-demethyl and N-oxide metabolites (21). The remaining portion of the dose was found in the feces, almost completely as unchanged drug (23). This fecal fraction was probably excreted via bile and/or gastrointestinal secretion.In the present study, the plasma and urinary pharmacokinetics of fleroxacin were investigated in cholecystectomized patients at steady state by using a regimen of 800 mg orally once a day. In addition, concentrations of unchanged drug and the two metabolites in T-drain bile were determined. Pharmacokinetic parameters for fleroxacin were changed only slightly compared with those reported for normal subjects. Biliary concentrations exceeded the corresponding concentrations in plasma and were adequate for prophylaxis or treatment of biliary tract infect...

The non-narcotic analgesic metamizol (noramidopyrine, dipyrone) is a typical prodrug. After oral administration, metamizol is completely hydrolysed in the gastro-intestinal tract to the pharmacologically active metabolite 4-methyl-amino-antipyrine (4-MAA). The main metabolic pathways for 4-MAA are consistent with 1) oxidation to 4-formyl-amino-antipyrine (4-FAA), and 2) demethylation to 4-amino-antipyrine (4-AA), which is further acetylated to 4-acteyl-amino-antipyrine (4-AcAA). The four metabolites of metamizol account for 65-70 % of the dose [1]. A previous investigation revealed that the pharmacokinetics of the metabolites was linear up to a dose of 1.5 g metamizol. An increase in dose to 3.0 g produced a greater increase in the areas under the serum concentration-time curve of 4-MAA, and a decrease in the formation of 4-FAA. The larger amount of 4-MAA resulted in a corresponding increase in the formation of further metabolites, such as 4-AA and 4-AcAA [2]. Since the conversion of 4-AA to 4-AcAA is produced by the polymorphic Nacetyl-transferase system [3], a greater deviation from linearity of 4-MAA pharmacokinetics can be assumed for slow acetylators than for rapid acetylators.The present study is based on reassessment of the data with regard to the acetylation ability of the participants and aims to give further information on the influence of acetylation phenotype on metabolite pharmacokinetics with increasing doses of metamizol.The participants were 15 healthy volunteers, who received single oral doses of 0.75, 1.5 and 3.0 g metamizol (1.5, 3 and 6 tablets Novalgin, Hoechst AG, Germany) on three different occasions, at 7 day-intervals [2]. The N. Bacracheva ([~). V. Vlahov Department of Clinical Pharmacology, Medical Faculty, University Hospital "Queen Giovanna", 8 Belo more Street, 1040 Sofia, Bulgaria serum and urine concentrations of the metabolites were determined using an HPLC method [4].Acetylation phenotyping of the participants was carried out according to the Zylber- Katz et al. (1992) [5] method, using the serum concentration ratio of 4-AcAA/4-AA 6 h after metamizol ingestion. Eight of the subjects were rapid [mean 6.77 (3.64)] and five were slow [mean 0.62 (0.18)] acetylators. Two of the participants were considered to be of intermediate type (mean 1.6) and were not included in the analysis.The influence of acetylation phenotype on the linearity of the pharmacokinetics of the metabolites of metamizol was evaluated using two parameters: the serum concentration-time curves (AUC) and the formation rates of the metabolites. The AUC's were calculated according to standard procedures [2]. The rates of formation of 4-FAA, 4-AA and 4-AcAA were expressed as clearance for production (eLm) of the metabolites and were calculated according to the formula CL m --Ae/AUCp, in which A e is the amount of metabolite excreted in urine, and AUCp is the area under the serum concentration-time curve of the precursor of the metabolite [6]. In the case of 4-MAA, non-renal clearance was used instead of the formation rat...

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.