CYP2C19 polymorphism affects single-dose pharmacokinetics of oral pantoprazole in healthy volunteers.

OBJECTIVES: Pantoprazole is metabolized by cytochrome P450 2 C19, which shows genetic polymorphism. The effect of CYP2C19 polymorphism on single-dose pharmacokinetics of oral pantoprazole in healthy volunteers was evaluated. METHODS: Pantoprazole pharmacokinetics was determined in 32 healthy volunteers after a 40-mg single oral dose of the drug. RESULTS: Carriers of CYP2C19*2/*2 (n = 2) were characterized by higher, starting from 3.5 h post dose, plasma concentrations of pantoprazole in comparison to wild-type (CYP2C19*1/*1, n = 6) volunteers. In subjects with CYP2C19*17/*17 genotype (n = 6) significantly lower plasma concentrations of the drug vs CYP2C19*1/*1 carriers, were observed from 3.0 h after oral pantoprazole administration. Carriers of CYP2C19*1/*17 (n = 6) and CYP2C19*2/*17 (n = 6) displayed concentration-time profiles comparable to wild-type subjects. CYP2C19*2/*2 volunteers showed a decrease in terminal elimination rate constant (λ(z)) by 83.3%, prolongation of terminal half-life (t(½)) by 572%, a rise in area under the concentration-time curve (AUC) and mean residence time (MRT) by 506% and 259% respectively. Heterozygotes, i.e.. CYP2C19*1/*2 vs CYP2C19*1/*1 were characterized by higher AUC (4.38 ± 1.00 mg·h/L vs 3.00 ± 1.02 mg·h/L, p < 0.05) and C(max) (2.13 ± 0.42 mg/L vs 1.61 ± 0.35 mg/L, p < 0.05) respectively. A significant reduction in MRT (3.83 ± 0.82 h vs 2.73 ± 0.23 h, p < 0.05) in carriers of CYP2C19*17/*17 vs CYP2C19*1/*1 genotypes was observed. Population modeling confirmed the influence of *1/*2, *2/*2, and *17/*17 genotypes on the pharmacokinetics of pantoprazole. The lowest population oral clearance was assessed in the carriers of genotype *2/*2 (3.68 L/h) and the highest value in subjects with genotype *17/*17 (31.13 L/h). CONCLUSION: These data suggest that CYP2C19 polymorphism is an important determinant of pantoprazole pharmacokinetics.

Pharmacokinetic-pharmacodynamic modeling of levodopa in patients with advanced Parkinson disease.

OBJECTIVES: The aims of the present study were to investigate the pharmacokinetic and pharmacodynamic (pk/pd) relationship of levodopa (l-dopa) in patients with advanced Parkinson disease (PD) and also to evaluate the effect of tolcapone on the pk/pd analysis of l-dopa in 1 patient with severe dyskinesias and fluctuations. METHODS: The pharmacokinetics (plasma concentrations of l-dopa and 3-O-methyldopa [3-OMD]) and motor effects (global score of the Unified Parkinson's Disease Rating Scale-III) of a single dose of l-dopa (plus the peripheral decarboxylase inhibitor 1:4) were determined in 14 patients with advanced PD. Patients were classified into 2 groups according to Hoehn and Yahr scale (stages 2 and 3). In 1 patient with severe dyskinesias and fluctuations, pk/pd of l-dopa were evaluated before and after coadministration of tolcapone at 100 mg 2 times daily for 1 month. The pk/pd analysis was based on an estimate of the maximal response model with a semiparametric approach to effect site equilibrium. RESULTS: The highest levels of l-dopa and 3-OMD were observed in patients with stage 3 of Hoehn and Yahr scale. We showed differences in the pk/pd parameters after coadministration of tolcapone in 1 patient as well as the clinical improvement.Univariate analysis showed some significant correlations (P < 0.05) between l-dopa pk/pd parameters and patients' age, duration of l-dopa treatment, and duration of the disease. Multivariate analysis adjusted for patients' age, sex, duration of the disease, and Hoehn and Yahr stage showed that presence of diphasic (dyskinesia-improvement-dyskinesia [DID]) dyskinesias was the only independent predictor of larger threshold level - EC50 (mean concentration at half maximal effect) of l-dopa (P = 0.034). CONCLUSIONS: The motor complications during long treatment therapy in patients with advanced PD especially with stage 3 Hoehn and Yahr scale were correlated to the higher plasma concentrations of l-dopa. In the presented study, patients with motor complications, especially with DID dyskinesias, exhibited a larger threshold level (EC50). The clinical improvement of a patient who received l-dopa and tolcapone can be explained by tolcapone-induced changes of peripheral and central l-dopa pharmacokinetics, which led to a decrease of l-dopa EC50 and 3-OMD concentrations. Our data indicate that pk/pd analysis may be helpful for monitoring the efficiency of therapeutic strategy applied in PD patients.

Assessment of liver function in children with acute lymphoblastic leukemia in remission.

PURPOSE: Acute lymphoblastic leukemia (ALL) is the most common malignant neoplasm in children. Antineoplastic treatment alone or with coexisting chronic viral hepatitis may permanently impair liver function. The aim of this study was to examine the effect of ALL and chronic viral hepatitis on the pharmacokinetics of lidocaine and its metabolite MEGX. MATERIAL AND METHODS: We enrolled 17 children and young adults with ALL in remission. Mean remission time was 61 +/- 30 months. Eleven patients were also infected with chronic viral hepatitis type B and/or type C. The control group comprised 12 healthy children. Lidocaine and MEGX pharmacokinetics were studied after intravenous administration of 1 mg/kg lidocaine. Serum samples were obtained at 15, 30, 60, 120, 240, and 360 min. from drug administration and were processed for separation by high-performance liquid chromatography. Statistical analysis was performed with Student's t-test. RESULTS: Elevated serum concentrations of MEGX 30 min. after lidocaine administration were observed in patients with ALL and hepatitis. The remaining pharmacokinetic parameters of lidocaine and MEGX did not differ significantly between groups. Our results suggest that pharmacokinetics of lidocaine and MEGX remain essentialy unaltered in ALL with coexisting chronic hepatitis.