Influence of CYP2D6 and CYP2C19 genetic polymorphism on the pharmacokinetics of tolperisone in healthy volunteers.

PURPOSE: This is the first study that connects pharmacokinetics of tolperisone with genetic polymorphism of the enzymes involved in its metabolism in human. We aimed to identify the influence of polymorphism of two main enzymes (CYP2D6 and CYP2C19) on pharmacokinetic profile of parent drug. METHODS: In a single-dose study, 28 healthy Caucasian male volunteers received an oral dose of 150 mg of tolperisone. The subjects were genotyped with respect to CYP2D6 and CYP2C19 enzymes. Plasma was sampled for up to 12 h post dose, followed by quantification of tolperisone by a fully validated HPLC-tandem mass spectrometry (MS/MS) method. The pharmacokinetic parameters were estimated using a non-compartmental method and compared statistically at level p < 0.05 across the genotyped groups. RESULTS: High variability (exceeded 100%) of main bioavailability parameters (AUCt, AUC(inf), C(max)) was observed in the whole group of subjects. An essential difference in the pharmacokinetics of tolperisone of quick metabolizers whose genotype expressed wild homozygote CYP2D6 *1/*1 with respect to heterozygous *1/*4 and *1/*5 subjects was demonstrated. The mean AUC(inf) was 2.1- and 3.4-fold higher in *1/*4 and *1/*5, respectively, than in *1/*1 subjects. In case of Cmax, the differences were greater and reached maximally 3.8 times (mean values 54.00, 98.85, and 205.20 ng/mL for CYP2D6 *1/*1, *1/*4, and *1/*5, respectively). Values of the parameters for the one subject that expressed *4/*4 genotype were even 8.5 times higher than in subjects with extensive or intermediate phenotype. Although CYP2C19 *1/*2 subjects had higher AUCt, AUC(inf), and Cmax values than *1/*1, no statistically significant differences were observed. Oral clearance (CL/F) significantly decreased by 65.7% in heterozygous *1/*2 relative to homozygous *1/*1 extensive metabolizers. CONCLUSION: In this study, we first demonstrated the effect of CYP2D6 polymorphism on pharmacokinetics of tolperisone in Caucasian subjects. The contribution of CYP2C19 enzyme seems to be less important.

[The effect of selenium and vitamin E on the healing process of experimental corneal lesions in the eye of the rabbit]. / Wplyw selenu i witaminy E na gojenie doswiadczalnego uszkodzenia rogówki w oku królika.

PURPOSE: Evaluation of antioxidants: selenium and vitamin E efficacy in the treatment of experimental corneal lesion. MATERIAL AND METHODS: Solution of selenium in 0.9% NaCl, concentration 0.01 g/L, to which vitamin E was added to obtain suspension of 2.5 g/L was used in 9 rabbits. The cornea was damaged by removing the epithelium from the central area of 7 mm diameter. To the right eye selenium solution with vitamin E was instilled. RESULTS: In two eyes in which antioxidants were used evident prompt healing of corneal ulceration was noticed. Mean lesion diameter in eyes treated with antioxidants was: on 1st day 5.44 mm, in 2nd day 1.61 mm and on the 3rd day 0.33 mm. In control eyes diameters were: 6.67 mm, 2.28 mm and 0.56 mm, respectively. CONCLUSIONS: Solution used in our study was tolerated very well. Faster healing process was noticed in eyes where antioxidants were used.

[Gentamicin kinetics in the blood and aqueous humor of the rabbit eye after intramuscular and subconjunctival administration]. / Kinetyka gentamycyny w krwi i cieczy wodnistej oka królika podanej domiesniowo i podspojówkowo.

Investigations were performed in rabbits which were given gentamycin intramuscularly and subconjunctivally. After subconjunctival application gentamycin passes quickly into the eye and its therapeutical level persists up to 1 hour. After intramuscular injection gentamycin is passing slower into the aqueous but persists there longer (the therapeutical level--up to 5.5 hours).

[Bioavailability of drugs applied to the eye externally]. / Dostepnosc biologiczna leków do oczu podawanych zewnetrznie.

There are following forms of the most frequently used ocular therapeutics: eye drops, ointments and inserts. In dependence on the physico-chemical properties of the therapeutical substance and the kind of disease one has to formulate the form of the drug in the manner to obtain its maximal bioavailability. By increasing their viscosity one can keep the watery solutions in the conjunctival sac for around 60 min. The time of the contact of the drug given in the form of suspension is limited mainly by the viscosity of the solution and the size of the molecules suspended in it. The ointments stay on the surface of the eye up to 2 hours. The ocular inserts secure a steady flow of the therapeutical substance up to 7 days. The compounds penetrate to the anterior chamber aqueous mainly through the cornea. Therefore the physiological factors of the lacrimal fluid, the properties of the cornea are influencing the penetration of the corneo-chamber barrier by the therapeutical substance.

Correlation between the total cholesterol serum concentration data and carbamazepine steady-state blood levels in humans.

The purpose of this study was to investigate the pharmacokinetics of carbamazepine at steady state, after multiple doses in patients with elevated serum cholesterol levels. Twelve patients participated in the investigation; patients were divided into two groups according to their total serum cholesterol levels. Each patient received multiple doses of carbamazepine 600 mg po once per day. Blood samples were collected and analyzed for carbamazepine by gas-liquid chromatography. The clearance concept was used to describe the pharmacokinetic behavior of carbamazepine in high and low cholesterol patients. The area under the plasma concentration-time curve was determined by the trapezoidal rule method. This value was used to determine the oral dose clearance. In this study, the authors found that the elevated serum cholesterol and elevated total lipids cause a decrease in drug concentration. The significantly higher values of the total body clearance of carbamazepine, obtained in patients with elevated serum cholesterol levels, may have significance in clinical practice.