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.

Prevalence of menstrually related migraine and nonmigraine primary headache in female students of Belgrade University.

OBJECTIVES: To determine prevalence and characteristics of menstrually related migraine and nonmigraine headache in female students of Belgrade University. METHODS: A questionnaire was administered to female students during randomly selected classes of the Schools of Medicine and Pharmacy. Diagnoses were assigned according to the criteria of the International Headache Society and MacGregor's stricter definition of "menstrual" migraine. RESULTS: Of 1943 female students (18 to 28 years old), 1298 (66.8%) had primary headaches. Among 1298 students with headache, 245 (12.6%) had migraine and 1053 (54.2%) had nonmigraine headache. The prevalence rates of migraine versus nonmigraine headache in relation to the menstrual cycle were: premenstrual, 0.9% versus 4.4%; menstrual, 1.5% versus 1.5%; menstrually associated, 6.1% versus 10.1%; menstrually unchanged, 2.7% versus 19.2%; and menstrually unrelated, 1.4% versus 18.9%. Female students with migraine had menstrually related attacks more frequently than students with nonmigraine headache (67.7% versus 29.5%). This difference was most prominent among students with menstrual migraine compared with students with menstrual nonmigraine headache (12.2% versus 2.7%). Exacerbation of migraine during menstruation was slightly more severe and more complex than exacerbation of nonmigraine headache. Female students with migraine versus nonmigraine headache did not differ significantly in age, age at onset of menarche, or age at onset of headache. Female students with migraine were significantly more likely to report a positive family history for migraine and menstrual migraine, severe attacks, reduced work activity, and aura. CONCLUSION: The results obtained are in accord with the prevailing opinion that there is a relationship between migraine and female sex hormones, and suggest that women with nonmigraine headache are also susceptible to hormonal fluctuations.

Urinary excretion of phenobarbital and its metabolite p-hydroxyphenobarbital in convulsing and non-convulsing patients.

As part of an investigation of phenobarbital (PB) pharmacokinetics in patients with status epilepticus (SE), urinary excretion of PB and its main metabolite, hydroxyphenobarbital (HPB), was studied in patients who had an episode of SE, as well as in non-convulsing ones. Eleven in-patients were studied:(group 1) five patients (4 M + 1 F; 48 +/- 28 years old; 64 +/- 6 kg body weight; mean +/- SD) with convulsive status epilepticus, and (group 2) six patients (5 M + 1 F; 37 +/- 13 years old; 71 +/- 15 kg body weight) with epilepsy, seizure-free at the moment of PB administration and without established anti-epileptic therapy. All subjects received a single intravenous dose of PB (15 mg/kg) at a rate of 100 mg/min. PB and HPB concentrations were measured by high performance liquid chromatography with UV detection at 220 nm in urine samples collected throughout 24 h. The comparison of pharmacokinetic parameters of urinary excretion of PB and HPB showed a statistically significant difference in the values of recovery of HPB and total barbiturate (higher values in the patients with SE) in 24 h urine. Differences in the excretion of PB between the two groups of patients--higher values in the patients who had had an episode of SE, and in urine flow--slightly elevated volumes in the same group, failed to reach statistical significance, probably due to the small number of participants in the study.

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.

Endogenous nucleosides in the guinea-pig eye: analysis of transport and metabolites.

This study investigates the transport of endogenous nucleosides and deoxynucleosides from the capillaries of the eye into the aqueous humour and the lens using the in situ vascular eye perfusion technique in the guinea-pig. The transport of [3H] adenosine and [3H] thymidine across the blood-aqueous barrier proved to be very rapid with a volume of distribution after 4 minutes perfusion reaching 11.9+/-3.0% and 9.93+/-1.1%, respectively. However, the transport of [3H] guanosine and [3H] cytidine was slower, with volumes of distribution reaching only 3.38+/-0.58% and 4.8+/-1.41%. The values for the entry of deoxyadenosine and deoxyguanosine were not significantly different from the values obtained for corresponding ribonucleosides (adenosine and guanosine) so that a change in the pentose sugar does not change the affinity of the nucleoside for the transport protein. Perfusion with a low sodium medium inhibited the transport of [3H] adenosine and [3H] thymidine into the aqueous humour. The presence of 800 nM NBTI also caused a decrease in adenosine transport into the aqueous humour, so that the volume of distribution after 2 minutes reached only 3.78+/-1.87%. These findings suggest that the transfer of adenosine across the blood-aqueous barrier has both concentrative and equilibrative components. The presence of 0.1 mM thymidine had no effect on the [3H] adenosine transport, whereas 0.1 mM of adenosine resulted in a marked decrease on the [3H] thymidine transport which suggests that the concentrative nucleotide transport is probably mediated by both cif and cit transport systems. The cellular uptake of nucleosides into the lens was very rapid and the volume of distribution of purine nucleosides was within the range of 30-50% whereas that for thymidine uptake was somewhat lower, reaching 20-30%. HPLC analysis of the eye structures in the guinea-pig showed that lens, vitreous body and the rest of the eye do not contain either free nucleosides or purine bases in detectable quantities, except for xanthine which was detected in aqueous humour at a concentration of 2.51+/-0.51 mM. However, serum of the anaesthetised guinea-pig did not contain xanthine in detectable amount so it seems that the metabolic degradation of the nucleosides in the guinea-pig eye progresses as far as xanthine, which is then accumulated in the aqueous humour.

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.

[Pharmacokinetic aspects of pediatric drug therapy]. / Farmakokineticki aspekti terapije u decjem dobu.

Pharmacokinetic processes of absorption, distribution, metabolism and excretion are modified during biological maturation and these changes give rise to two characteristics of pediatric therapeutics: drug pharmacokinetics both changes throughout childhood and differs from adults, and most drugs show large interpatient variability in this patient population. Therapeutic problems that arise are potentially solvable by pharmacokinetic approach, where therapeutic monitoring is necessary in order to individualize therapy and define drug pharmacokinetics in special pediatric groups and situations. To realize this goal, good collaboration between the clinician and therapeutic consultant is extremely important. The consultant has to understand pharmacokinetic principles and apply them in therapy. Determination of initial drug doses can be done by several methods based on age, body mass or surface area, although from pharmacokinetic aspect the method based on volume of distribution value in adults (Vd in l/kg) is recommended.

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.

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.

Serum erythropoietin levels in hemodialysed patients after administration of recombinant human erythropoietin.

In anemic patients on regular hemodialysis (HD), correction of anemia with recombinant human erythropoietin (rHuEpo) administered intravenously (iv) or subcutaneously (sc) was followed over a 2-month period. Monitoring serum Epo post-dose concentrations after the first iv rHuEpo injection and following another regular injection after 2 months of therapy with rHuEpo iv in 9 patients showed that the Epo elimination half-life was reduced from 7.48 h to 4.68 h. In the same patients the initially low percentage of erythroblasts and mature erythroid progenitors increased during 2 months of rHuEpo therapy. Because Epo molecules bound to Epo receptors are internalized in target cells we suggest that the expansion of the Epo responsive cell pool could explain the shorted Epo elimination time after 2 months of rHuEpo treatment. By monitoring serum Epo concentration following sc rHuEpo injection in 7 HD patients it was found that the modest increase in serum Epo levels (30-60 mU/ml) was sufficient to correct anemia.

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.

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.

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.

Dependence of the renal excretion of theophylline on its plasma concentrations and urine flow rate in asthmatic children.

The dependence of the renal excretion of theophylline on its plasma concentration and urine flow rate has been investigated in asthmatic children of either sex. One group (age 12.25 +/- 0.80, mean +/- s.d. n = 8) was given aminophylline intravenously (i.v.), while another (age 10.00 +/- 3.64 n = 14) was given a sustained release preparation of theophylline orally (single dose and repeated doses). Unchanged drug (11.6% +/- 1.75) was excreted in the urine corresponding to a renal clearance of 10.6 +/- 1.6 mL h-1kg-1. Time dependence of the renal clearance of theophylline was found only after i.v. administration. Dependence of the renal clearance on urine flow rate was found both after i.v. administration and at steady state, but not after a single oral dose of theophylline. After oral administration, renal clearance of theophylline was higher at steady state than after a single dose (0.58 +/- 0.06 L h-1 kg-1 vs 0.23 +/- 0.03 L h-1 kg-1), while urine flow rate was lower (1.1 +/- 0.5 mL min-1 vs 1.8 +/- 0.9 mL min-1). High correlation of theophylline plasma concentration and theophylline excretion rate was obtained in 10 of 14 patients after administration of a single oral dose of the preparation (r = 0.8567 to 0.9830). There was no dose dependence of the renal clearance of the drug either after a single dose, or at steady state.

Pharmacokinetics of theophylline in hyperthyroid and hypothyroid patients with chronic obstructive pulmonary disease.

The pharmacokinetics of theophylline was investigated in five hyperthyroid, five hypothyroid, and five euthyroid patients, all with chronic obstructive pulmonary disease. Wide individual variability was found in theophylline kinetics, but the rate of elimination of theophylline was significantly higher in hyperthyroid, and lower in hypothyroid patients than in the euthyroid patients (kel = 0.155, 0.060 and 0.107 h-1, respectively). The values for clearance and volume of distribution were not consistently changed compared with those in the euthyroid group, although all the parameters except AUC were significantly different in hyperthyroid and hypothyroid patients. There was a positive correlation between both thyroxine and triiodothyronine serum concentrations and total body clearance of theophylline (r = 0.795 and r = 0.791, respectively). It is concluded that in spite of the wide interindividual variability and the relatively small differences in the pharmacokinetics of theophylline in thyroid dysfunction compared with the euthyroid status, these differences have to be considered in certain clinical situations, as they may require changes in the therapeutic regimen for administration of theophylline in hyperthyroid or hypothyroid patients.