Impact of age, weight and concomitant treatment on lamotrigine pharmacokinetics.

WHAT IS KNOWN AND OBJECTIVE: Lamotrigine metabolism may be substantially altered with concomitant administration of valproic acid and/or carbamazepine. Such alterations may require the adjustment of lamotrigine dose to ensure optimal treatment efficacy and safety. METHODS: The extent of lamotrigine interactions was investigated dependent on age, gender, weight and dose of concomitant carbamazepine and/or valproic acid in 65 patients with epilepsy. Lamotrigine plasma steady-state oral clearance (CLss/F) and area under the curve (AUCss) were calculated from the dose of drug, average steady-state concentration (Css) and interval of administration. Multiple regression analysis was used for the identification and quantification of factors that influenced lamotrigine pharmacokinetics. RESULTS AND DISCUSSION: Age and dose of carbamazepine and valproic acid had significant influence on lamotrigine CLss/F and AUCss. Carbamazepine was associated with a dose-dependent increase and valproic acid with a dose-dependent decrease of lamotrigine metabolism rate. The effect of carbamazepine was more pronounced. Younger patients were expected to metabolize lamotrigine more rapidly whereas overweight patients may be less susceptible to interactions. Gender had no influence on lamotrigine pharmacokinetics. WHAT IS NEW AND CONCLUSION: The efficacy and safety of lamotrigine may be altered by concomitant administration of carbamazepine and valproic acid. The models developed may be useful for estimating doses of lamotrigine for individual patients to minimize clinically significant interactions. Therapeutic monitoring is advisable when those drugs are used concomitantly.

Comparison of liquid chromatography with fluorescence detection to liquid chromatography-mass spectrometry for the determination of fluoxetine and norfluoxetine in human plasma.

A comparison study on fluoxetine (FL) and norfluoxetine (NORFL) quantitation in human plasma was carried out between the recently developed liquid chromatographic method with fluorescence detection (LC-FLD) and an earlier established liquid chromatography-mass spectrometry (LC-MS) laboratory procedure. Comparative method evaluation was based on the analysis of plasma samples obtained from Parkinsonian patients receiving 20mg of FL per day. The LC-FLD method involves a two-step liquid extraction procedure without any derivatization, followed by direct chromatography on a Zorbax C8 reversed-phase column. The analytical results are discussed in terms of the method validation and the corresponding experimental protocol (r>/=0.998; CV<9%; LOQ 20 microg/l). There was good correlation between FL, as well as NORFL, plasma levels as determined by the LC-MS and LC-FLD techniques (r=0.9597, N=16 and r=0.9852, N=14 for FL and NORFL, respectively). The results confirm that direct FL/NORFL fluorimetric determination is acceptable for routine use in pharmacokinetic and clinical studies.

Liquid chromatographic-mass spectrometric method for the determination of fluoxetine and norfluoxetine in human plasma: application to clinical study.

A selective, sensitive, simple, and rapid method for the simultaneous determination of fluoxetine (FL) and norfluoxetine (nor-FL) was developed and validated, and further applied to analyze plasma samples obtained from FL-treated patients with Parkinson disease (n = 18). After one step liquid-liquid extraction with ethyl acetate, plasma samples were chromatographed on a C8 column. The mobile phase was acetate buffer and acetonitrile (40:60 v/v). Determination of FL and nor-FL was performed with MS detection in selective ion monitoring (SIM) mode, so the other components did not interfere with this assay. FL, nor-FL and flumazenil as internal standard were eluted in 6 min. Recoveries ranged from 89.7 to 96.6% and from 80.2 to 85.3% for FL and nor-FL, respectively. The limit of quantitation under described conditions was 2.5 microg/l for FL and 10 microg/l for nor-FL. The method was found to be reproducible with coefficient of variation less than 9%. The parameters of the method were found to be acceptable to enable its routine use for clinical studies. The method was employed to analyze the Parkinsonian patients' plasma samples. A great deviation in plasma concentrations of FL and nor-FL found among 18 studied patients indicates high pharmacokinetic variability of the drug. Obtained results also indicate absence of the influence of Parkinson disease on the drug disposition.

Comparative pharmacokinetics and bioavailability of two cotrimoxazole preparations.

The objective of this study was to assess both pharmacokinetic properties and bioavailability of a newly developed cotrimoxazole preparation (Bioprim tablets, 80 mg of trimethoprim/400 mg sulfamethoxazole), in comparison with a reference preparation commercially available (Bactrim tablets, 80 mg of trimethoprim/400 mg of sulfamethoxazole). The pharmacokinetics and bioavailability of cotrimoxazole from these preparations were compared in an open randomized crossover study in 12 healthy males. Plasma concentrations of trimethoprim and sulfamethoxazole were measured by HPLC after protein precipitation. Noncompartmental pharmacokinetic analysis was performed on the plasma concentration-time data. The obtained pharmacokinetic values (Cmax, tmax, beta, t1/2 beta, CL, Vd, AUC36, AUC infinity) of both trimethoprim and sulfamethoxazole determined in our study agreed with values reported in the literature. Westlake's and Nonparametric probability tests with the 90% confidence intervals, for both trimethoprim and sulfamethoxazole gave the differences within 80 and 120%, for all necessary measures (Cmax, tmax and AUC infinity). Statistical analysis of the data has shown that the preparations have similar pharmacokinetic profiles and therefore can be considered equally bioavailable.

The influence of lithium on fluvoxamine therapeutic efficacy and pharmacokinetics in depressed patients on combined fluvoxamine-lithium therapy.

The influence of lithium on fluvoxamine therapeutic efficacy, plasma concentrations and pharmacokinetics was studied in 12 depressed inpatients. Six patients were on fluvoxamine monotherapy and six were on combined fluvoxamine-lithium therapy. The treatment response was determined using 17-item Hamilton Rating Scale for Depression. Blood samples were collected during 48 h after a single dose administration of 100 mg fluvoxamine, and five times at steady state after repeated doses of 100 mg fluvoxamine per day. The evaluation of 17-item Hamilton Rating Scale for Depression Scores showed a significant clinical improvement 2 and 4 weeks after the beginning of the therapy in both groups (p < 0.01). However, 2 weeks after the administration of the drug(s) had started, significant differences (p < 0.05) in efficacy between the two treatments in favour of the fluvoxamine-lithium combination were found. Plasma concentrations of fluvoxamine were measured by high-performance liquid chromatography. The comparison of the measured concentrations of fluvoxamine showed a similar course of the plasma concentration-time curves in both groups of patients. Pharmacokinetic parameters of fluvoxamine did not show any significant difference on the comparison between the groups. According to the results from this study, it is evident that lithium does not affect plasma concentrations and pharmacokinetics of fluvoxamine in depressed patients on concomitant treatment with these two drugs. However, the effect achieved with the combination was better.

Clinical response and plasma concentrations of amitriptyline and its metabolite-nortriptyline in depressive patients.

Although many attempts have been made, to date no convincing evidence exists of a relationship between plasma concentrations of amitriptyline (AT), its active metabolite nortriptyline (NT) and clinical response. Fifteen patients with primary depression (according to DSM-IV) were divided in two groups according to given doses: (I) 6 patients received 3 x 50 mg of AT daily; and (II) 9 patients received 3 x 25 mg of AT daily, for 6 weeks. The clinical status was determined with Hamilton Depression Rating Scale. Both investigated doses were therapeutically effective. AT and NT plasma concentrations were assayed by high performance liquid chromatography. Following administration of 3 x 50 mg of AT daily, the correlation of concentrations of AT, NT, total AT + NT and clinical response were rAT = -0.702 (P < 0.1), rNT = -0.761 (P < 0.1), rAT + NT = -0.741 (P < 0.1). The linear and very high correlation were also present with concentrations of AT, NT, total AT + NT and clinical response in depressive patients on 3 x 25 mg AT daily: rAT = -0.785 (P < 0.02), rNT = -0.811 (P < 0.01), rAT + NT = -0.848 (P < 0.01). Our results support a high correlation between AT/NT plasma concentrations and clinical response indicating that therapeutic monitoring of AT and its metabolite, NT, can provide eventual clinical response.

Correlation of mono and combined amitriptyline/lithium therapy with therapeutic and side effects.

The role of lithium in combination with tricyclic antidepressants (TCA) used in the treatment of unipolar depression has been much less studied than in the case of bipolar disorders. The aim of this study was to compare the therapeutic and side effects with doses and plasma concentrations in the patients with major (unipolar) depression (DSM-III-R criteria) treated by amitriptyline combine (At+Li) and mono-therapy. All three, of these regimens, were therapeutically effective, but after 6 weeks combined (At+Li) therapy showed the absence of the increased number of side effects.

The relationship between phenazone (antipyrine) metabolite formation and theophylline metabolism in healthy and frail elderly women.

The influence of aging on the metabolism of phenazone (antipyrine), and the relationship between the formation of 3 phenazone metabolites and the metabolic clearance of theophylline in healthy and frail elderly women, were examined. Whereas the elimination half-life did not change, clearance of phenazone decreased by about 50% with age in healthy women receiving phenazone without theophylline. However, the summation of the urinary recovery of phenazone and the measured metabolites, expressed as percentage of the phenazone dose, was lower in the healthy elderly (37 +/- 9% vs 74 +/- 15%). In both healthy and frail females the clearance of formation of 4-hydroxy-phenazone and the metabolic clearance of theophylline correlated strongly (r = 0.93 and 0.90, respectively). In non-healthy elderly females, strong correlations were also observed between the other metabolic pathways of phenazone and the metabolic clearance of theophylline. Coadministration of theophylline in the elderly increased the percentage of the phenazone dose excreted as the measured metabolites. A considerably higher interindividual variability in the disposition of phenazone and theophylline was observed in the frail elderly women. This high degree of variability in drug metabolism may be one of the explanations for the problems often occurring after drug prescription in the elderly.

An improved gas chromatographic determination of valproic acid and valpromide in plasma.

A newly, improved analytical method for determination of valproic acid (VPA) and valpromide (VPD) in human plasma was developed. The method is based on gas chromatographic determination with flame ionization detection, after chloroform extraction of the drugs from plasma. Caprylic acid was used as an external standard. With the extraction procedure chosen, high recoveries for both VPA and VPD were achieved (98-102%), with correlation coefficient of 0.9998 for VPA and 0.9996 for VPD. Sensitivity of the method was also high (2 ng or 2 mg/L), while the linearity was obtained over the range of 5-150 mg/L, with high correlation for both drugs (0.9997 and 0.9995 for VPA and VPD, respectively). Reproducibility of the method was documented with low values of coefficients of variation, both inter-assay and day-to-day values (1.4-4.4 and 1.7-3.7 for VPA and 2.1-5.0 and 2.6-5.1 for VPD, respectively). The method has been used to follow VPA plasma levels in adult epileptic patients on sodium valproate therapy.

Mass spectrometric investigation of 2-aminopropiophenones and some of their metabolites.

Complex metabolic mixtures of 2-aminopropiophenones, obtained both after in vitro and human in vivo metabolism of these compounds, have been investigated using both mass spectrometry and gas chromatography/mass spectrometry. The mass spectrometric fragmentation schemes of the compounds have been proposed and verified. The schemes are based on the characteristic fragments obtained by alpha-cleavage of these compounds using direct inlet mass spectrometry or gas chromatography/mass spectrometry. These findings were confirmed with chemical ionization mass spectrometry, when quasi-molecular (MH+) ions were obtained as the highest relative abundance ions for all the compounds investigated, and were used in metabolic investigations of 2-aminopropiophenones.

When is the use of alternative biological fluid in pharmacokinetics possible; an example of theophylline.

Special interest in alternative approach to clinical pharmacokinetic research nowadays, especially in pediatric practice, is concerned on biological fluids obtainable by non- invasive methodology. Saliva and urine are the most interesting fluids in this approach. The possibility of using saliva and urine was investigated and evaluated in theophylline (Th) therapy, both in asthmatic children and adults. The investigation on drug presence in saliva (asthmatic children and adults) and in urine (asthmatic children) during Th therapy, confirmed good correlation between saliva and plasma, and between urine and plasma, and provided reliable basis for the conclusion that both saliva and urine can be used in pharmacokinetic research of The elimination in asthmatic children. Only saliva was investigated in adult patients and it was found that it can be used as alternative biological fluid in pharmacokinetic research, but with less reliability than in children.

Single dose and steady state pharmacokinetics of valproic acid in adult epileptic patients.

The pharmacokinetics of valproic acid was studied in ten adult epileptic patients (five f + five m, 19-48 years; 28 +/- 12, mean +/- SD, and body mass 45 to 70 kg; 61 +/- 7, mean +/- SD) both after single dose and at the steady state. Sodium valproate was given in a 900 mg single oral dose on the first day of therapy, followed by 3 x 300 mg/day during the three subsequent days (at the intervals of 7, 8 and 9 h). During the first day, plasma was obtained just before the drug was given, and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10 and 12 h after drug administration. On the fourth day of therapy (at steady state), plasma was obtained just before the next dose and 3 h after the drug administration. The plasma concentrations of valproic acid were measured by gas chromatography with flame ionization detection, after extraction with chloroform. The pharmacokinetic parameters, necessary to define the pharmacokinetics of valproic acid, were calculated both after single dose: Cmax, tmax, kel, t1/2, Vd, AUC and Cl, and at steady state: Cminss Cmaxss and Fl%. These parameters, as well as plasma levels of the drug, were used to describe the pharmacokinetic behaviour of valproic acid under these clinical conditions, and mainly were in agreement with the values published in the literature.