Background Increasing oral doses of mibefradil (10 to 320 mg) decrease its apparent oral clearance; however, intravenous doses up to 80 mg do not reduce its systemic clearance. This study aimed to understand the mechanisms underlying the zero-order kinetics of mibefradil. Methods A group of 10 normotensive volunteers received 50 mg/day oral mibefradil for 8 days and, on days 1 and 8, 5 mg deuterated mibefradil by infusion. Ten additional volunteers observed the same protocol with a daily oral dose of 100 mg mibefradil. Serial blood samples were withdrawn, and mibefradil plasma concentrations were assayed by liquid chromatography–mass spectrometry. Blood pressure and heart rate were measured for 4 hours, and an ECG was performed 2 hours after drug administration. Results Repeated oral administration of 50 mg mibefradil generated zero-order kinetics secondary to a decrease in mibefradil systemic clearance. Compared with the 50-mg dose, single and repeated oral doses of 100 mg further decreased mibefradil clearance. Mibefradil bioavailability was not affected by increasing mibefradil doses. Mean diastolic blood pressure was decreased by single and repeated doses of 100 mg to the same extent. Repeated doses of 100 mg reduced heart rate and prolonged the PR and QTc, changes that were associated with mibefradil plasma concentrations. Conclusions Repeated doses of 50 mg or doses of 100 mg mibefradil generated zero-order kinetics secondary to a decrease in hepatic extraction of the drug. Zero-order kinetics did not affect the response-concentration relationship of mibefradil. (Clin Pharmacol Ther 2000;67:249–57.) Clinical Pharmacology & Therapeutics (2000) 67, 249–257; doi: 10.1067/mcp.2000.104616
Previous long-term studies have shown that in the pineal gland of rats melatonin synthesis is subject to infradian rhythms with periods between 4 and 7 days. Since in these studies melatonin-related parameters were measured at one timepoint of a 24-hr cycle only, the aim of the present investigation was to extend these experiments by more frequent sampling, to characterize the infradian rhythmicity in more detail. Male Sprague-Dawley rats kept under a light schedule of LD 12:12 (lights on at 0700) were killed at 6-hr intervals on 8 consecutive days. After decapitation the pineal gland was rapidly dissected out, followed by measurements of one of the melatonin-forming enzymes, serotonin N-acetyltransferase (NAT) activity. It was found that pineal NAT activity exhibited the well known day/night rhythm, i.e. low activity during daytime and strikingly enhanced activity at night, during the first 4 days of the experiment. On the fifth night (from Saturday to Sunday) an unusually high NAT peak occurred at 2400 hr, followed by two atypical 24-hr cycles. In the first cycle the midnight and 0600 hr values were equal and in the second cycle the 0600 hr value was significantly higher than the midnight value. To investigate whether the unusually high NAT peak was a single event or not, four additional short-term experiments were carried out at 2400 hr on 4 consecutive weekends, from Friday to Monday. In each of the four 4-day experiments a distinctly higher peak of NAT activity was found on Saturday, but with time the peaks became less prominent. It is concluded that the extremely high peaks of NAT activity in the rat pineal gland may result from beat frequencies that occur by superimposition of rhythms with different period lengths.
The efficacy of multiple oral administration of the renin inhibitor Ro 42-5892 [(S)-α-[(t-butylsulfonyl)-methyl]hydrocinnamamido] -N-[1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-imidazole-4-propionamide] was studied. Forty-nine patients with moderate essential hypertension were randomly assigned to three groups that entered an 8-day double-blind oral treatment period: daily administration of placebo (group A), 300 mg Ro 42-5892 (group B), or 600 mg Ro 42-5892 (group C). Four hours after the last oral drug intake, placebo was administered intravenously to subjects in group A and 100 mg Ro 42-5892 was administered intravenously to subjects in groups B and C. Sitting systolic and diastolic blood pressures were measured on days 1 and 8 with a blood pressure device. On day 1, systolic blood pressure maximally decreased by 13.3 ± 9.3, 20.2 ± 11.2, and 24.1 ± 11.3 mm Hg in groups A, B, and C, respectively (mean ± SD; p < 0.01 for group A versus group C). Diastolic blood pressure maximally decreased 9.4 ± 5.7, 13.9 ± 8.7, and 11.8 ± 5.7 mm Hg (difference not significant). On day 8, systolic blood pressure maximally decreased 19.5 ± 16.5, 26.5 ± 17.4, and 30.5 ± 18.4 mm Hg and diastolic blood pressure maximally decreased 14.8 ± 5.0, 16.2 ± 9.0, and 17.9 ± 12.7 mm Hg (difference not significant) compared with pretreatment values. Intravenous drug administration did not further reduce blood pressure, suggesting that the mode of action and not the low bioavailability was the limiting factor for the low efficacy. Clinical Pharmacology and Therapeutics (1993) 54, 567–577; doi:10.1038/clpt.1993.189
A metaanalysis was conducted on data from 172 subjects (healthy volunteers and uninfected patients) included in 10 pharmacokinetic studies of fleroxacin after oral administration. The objectives of this analysis were (i) to estimate the typical values of two key pharmacokinetic parameters, clearance over systemic availability (CL/F) and volume of distribution over systemic availability (V/F), after the administration of therapeutic doses and (ii) to study qualitatively and quantitatively the factors which influence the elimination and distribution of fleroxacin. The main pharmacokinetic parameters, CL/F and V/F, were analyzed separately by a standard two-stage approach. The covariates investigated were predicted creatinine clearance (CLCR), age, gender, body surface area, body weight, and lean body weight (LBW). The predicted CL/F and V/F were 83.5 ml/min and 101 liters, respectively, for a typical male subject (CLCR, 70 ml/min; LBW, 54 kg; age, 54 years). Modeling of CL/F indicated that this parameter increases linearly with CLCR, decreases linearly with age, and is 10.8 ml/min lower in females than in males. The best model for V/F showed a linear increase with LBW and a linear decrease with age. V/F was found to be 20.4 liters greater in males than in females. In conclusion, this metaanalysis has shown that CLCR, age, and gender influence the elimination of fleroxacin from the body, whereas V/F is influenced by LBW, age, and gender.
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