Pharmacokinetic profile of a modified release formulation of trimetazidine (TMZ MR 35 mg) in the elderly and patients with renal failure.

Objectives - To study the effect of age and renal function on the pharmacokinetic profile of a modified release tablet of trimetazidine (TMZ MR 35 mg) administered twice daily.Methods- Study 1: Twelve healthy elderly subjects (CL(creat) 72+/-8 ml/min, 72+/-4 years mean+/-SD) and eight young volunteers (CL(creat) 134+/-18 ml/min, 25+/-8 years) received TMZ MR 35 mg b.i.d. (eight doses). Study 2: eight patients with severe renal failure (CL(creat.) 17+/-5 ml/min, 54+/-10 years), five patients with moderate renal failure (CL(creat.) 39+/-6 ml/min, 54+/-15 years) and eight volunteers (CL(creat.) 104+/-17 ml/min, 53+/-9 years) received TMZ MR 35 mg b.i.d. (patients: ten doses, volunteers: eight doses). Serial blood and urine samples were obtained following administration of the last dose in each study. TMZ plasma and urine concentrations were determined by gas chromatography (NPD-detector). The resulting data were analysed using standard non-compartmental pharmacokinetic methods.Results- Study 1: Elimination half-life of TMZ was significantly longer and renal clearance significantly lower in the elderly subjects. Study 2: In patients with either moderate or severe renal failure, exposure (AUC(0-24)) was significantly increased and renal clearance (CL(R)) was significantly decreased. Significant correlations were observed between CL(creat) and CL(R) (r=0.94) and between CL(creat) and AUC(0-24) (r=-0.94). Conclusion - With repeated administration of TMZ MR 35 mg b.i.d., a decrease in CL(creat) is directly related to a decrease in CL(R) and results in an increase in exposure to TMZ.

Methylprednisolone infusion during acute exacerbation of MS: plasma and CSF concentrations.

Plasma and CSF concentrations of methylprednisolone (MP), after a high-dose intravenous administration (1,500 mg) prescribed to patients presenting acute exacerbation of multiple sclerosis, were measured. A plasma pharmacokinetic study with 1 CSF sample was performed in 9 patients and 4 other patients had a single plasma sample at the time of lumbar puncture. MP plasma kinetics were similar between patients. Pharmacokinetic parameters were very close to previous published values obtained in normal volunteers or patients with rheumatoid disease. Passage of MP into the CSF was delayed since mean plasma/CSF ratio dropped dramatically from 150 at the 2nd h to 25 at the 3rd h after starting infusion. CSF concentrations of MP were high with a mean reaching 522 micrograms/l at the 6th h. The high levels of CSF concentrations suggest that MP may have powerful pharmacological effects within the CNS. No correlation was found between CSF concentration and the clinical response to steroid therapy. The issues related to previous data on clinical, biological and radiological effects of high-dose intravenous MP are discussed in the light of our results.

Liquid-chromatographic determination of propisomide and its mono-N-dealkylated metabolite in plasma and urine.

We describe a "high-performance" liquid-chromatographic assay for simultaneously determining propisomide and its mono-N-dealkylated metabolite in plasma and urine. After extraction with dichloromethane at alkaline pH, the unchanged drug, its metabolite, and the internal standard are separated by liquid chromatography on a reversed-phase column and the absorbance of the eluate is measured at 254 nm. Selectivity, sensitivity, and reproducibility are excellent. Results are similar to those by gas chromatography for propisomide but, in addition, the metabolite can be simultaneously measured in the same clinical sample. We also report results by this method for blood and plasma samples from a volunteer receiving a single 200-mg dose of propisomide.

Butofilolol pharmacokinetics in chronic renal insufficiency.

The pharmacokinetics of butofilolol, a new beta-blocking drug used in the treatment of hypertension, were investigated in 9 patients with varying degrees of renal impairment (creatinine clearance ranging from 65 ml/min to 6.6 ml/min). The drug was administered as a single oral 100-mg dose. Plasma and urine concentrations of the parent drug were measured. The pharmacokinetic parameters of butofilolol calculated from examination of patients with renal failure were compared to those obtained from healthy subjects. Renal failure was found to be associated with a marked increase of the areas under the plasma concentration-time curves of the parent drug whereas its elimination rate constant tended to increase, especially in severe renal failure. A highly significant relationship between the amounts of unchanged drug excreted in urine and the creatinine clearance was observed (r = 0.90, p less than 0.001). The higher plasma levels of the parent drug observed in renal failure might be due to a decrease in the first-pass hepatic extraction of the drug. But these changes in plasma clearance were probably counteracted by modification of the volume of distribution, so that the net result of these alterations was a slight increase in the elimination half-life.

Pharmacokinetics of butofilolol (CAFIDE) after repeated oral administration in man.

The pharmacokinetics of butofilolol, a new beta-blocking drug, was studied in 6 healthy subjects. Plasma concentrations and urinary excretion of the unchanged drug were determined after a single 100-mg oral administration, and also during chronic treatment (100 mg/day for a week) and after the last dose. Maximum plasma concentrations were observed 2 to 3 h after drug administration and varied between the subjects (120 to 430 ng/ml). The apparent volumes of distribution were large, ranging between 200 I and 500 I, and the apparent clearances of elimination appeared to be intermediate between 40 and 70 l/h. Drug elimination in the urine (about 4% of administered dose) occurred by filtration, tubular secretion and pH-sensitive reabsorption following a non-linear process. However, pharmacokinetic parameters remained constant during chronic treatment, since urinary elimination of the parent drug was too low to influence its pharmacokinetic profile. In addition, a high correlation was found between plasma levels of butofilolol and the effect of the drug on resting heart rate, while a slight effect on diastolic blood pressure could be discerned.

Comparison of gas chromatographic--electron-capture detection and high-performance liquid chromatography for the determination of butofilolol in biological fluids.

Two selective and sensitive methods for the quantitative analysis of butofilol in human plasma and urine are discussed. The first method is a gas chromatographic assay with electron-capture detection using extraction with toluene, several clean-up procedures and derivatization. The second method is based on high-performance liquid chromatography and a single extraction with dichloromethane. The two assay methods were applied to the determination of the same human plasma samples after administration of a single, oral 200-mg dose of butofilolol. A good correlation between the results (inter-laboratory comparison) is obtained, validating both techniques.

The pharmacokinetics and availability of niflumic acid in humans.

The pharmacokinetic parameters and relative availability of niflumic acid in two different pharmaceutical preparations were studied in 12 subjects after a single oral administration. Total plasma clearance averaged 45 ml/min, and the half-life of elimination approximately 2 h, giving a distribution volume of 0.12 l/kg on the average. The values of these pharmacokinetic parameters were in agreement with the general characteristics of this type of substance, a weak acid strongly bound to plasma proteins. Comparison of the systemic availability of the two oral forms showed no difference; they were probably close to 100%.