Population pharmacokinetic analysis of ciprofloxacin in the elderly patients with lower respiratory tract infections.

The aims of the study were to develop a population pharmacokinetic model of ciprofloxacin (CPX) in the elderly patients and to examine the impact of patient-dependent variables on pharmacokinetic parameter values of this drug. The study was conducted in a group of 44 patients at the age of 44-96years, hospitalized due to pneumonia lobaris or bronchopneumonia. Patients received CPX at a dose of 200mg every 12h as a constant rate infusion over 0.5h. Concentrations of CPX in serum were measured by HPLC with UV detection. Population pharmacokinetic analysis revealed that CPX concentration versus time data were best described by a one-compartment model. The mean values of volume of distribution and clearance of CPX in the patients above 65years of age were 78.41±13.17L and 18.39±4.15L/h, respectively. The creatinine clearance influenced CPX clearance according to the equation: CLCPX (L/h)=8.0+0.21·CLCr, while the volume of distribution of CPX was dependent on the body weight of the patient as follows: VdCPX (L)=22.72+0.86·WT. In summary, the developed population model can be used to assess the pharmacokinetic parameters of CPX in the elderly patients and to select on the basis of these parameters and MIC values an optimal dosage regimen of this drug.

Determination of linezolid in human serum by reversed-phase high-performance liquid chromatography with ultraviolet and diode array detection.

A high-performance liquid chromatographic (HPLC) method with UV and DAD detection for the quantitative determination of linezolid in human serum was developed in present work. Chromatography was carried out by reversed-phase technique on a RP-18 column with a mobile phase composed of 50 mM phosphate buffer and acetonitrile (76 : 26, v/v), adjusted to pH 3.5 with orthophosphoric acid. Serum samples were deproteinized with methanol centrifuged and then, the supernatant was analyzed using HPLC procedure. No interference was observed at the retention times of linezolid from blank serum or ten commonly used antibiotics. A concentration range from 0.50 to 30.0 g/mL was utilized to construct calibration curves. The lower limit of detection was determined to be 0.1 microg/mL of serum for both detectors. The lower limit of quantification of 0.25 microg/mL (CV = 2.6%) was established for determination using HPLC-UV and 0.5 microg/mL (CV = 5.42%) for HPLC-DAD. The recovery of linezolid was approximately 100%. Intra-day accuracy ranged from 0.97 to 12.63% and 0.74 to 10.85% for HPLC-UV and HPLC-DAD method, respectively. Intra-day precision was less than 4.69% for HPLC-UV and less than 5.42% for HPLC-DAD method. Tests confirmed the stability of linezolid in serum during three freeze-thaw cycles and during long-term storage of frozen serum for up to 6 weeks; in extracts it was stable in the HPLC autosampler over 24 h. Statistical analysis by Student's t-test showed no significant difference between the results obtained by these two methods. In summary, these methods will be used and adapted for infected patients in intensive care unit, to determine linezolid serum concentrations in order to know the pharmacokinetic profiles of linezolid.

Liquid chromatography-mass spectrometry method for the analysis of 1,4-dimethylpyridinium in rat plasma--application to pharmacokinetic studies.

A sensitive and specific liquid chromatography electrospray ionization-mass spectrometry method for determination of 1,4-dimethylpyridinium (1,4-DMP) in rat plasma has been developed and validated. Chromatography was performed on an Aquasil C(18) analytical column (4.6 × 150 mm, 5 µm, Thermo Scientific, Rockford, IL, USA) with isocratic elution using a mobile phase containing acetonitrile and water with an addition of 0.1% of formic acid. Detection was achieved by an Applied Biosystems MDS Sciex (Concord, Ontario, Canada) API 2000 triple quadrupole mass spectrometer. Electrospray ionization was used for ion production. The limit of detection in the single ion monitoring mode was found to be 10 ng/mL. The limit of quantification was 50 ng/mL. The precision and accuracy for both within-day and between-day determination of 1,4-dimethylpyridinium was 2.4-7.56 and 90.93-111.48%. The results of this analytical method validation allow pharmacokinetic studies to be carried out in rats. The method was used for the pilot study of the pharmacokinetic behavior of 1,4-DMP in rats after intravenous administration.

Capillary electrophoresis/frontal analysis versus equilibrium dialysis in dexamethasone sodium phosphate-serum albumin binding studies.

Plasma protein binding of drugs may have significant effect on its pharmacodynamic, toxicological and pharmacokinetic properties, since only the free drug can pass across biological membrane and get to its specific site of action. Many drugs show a high affinity to albumin which is the most abundant plasma protein. In the present study capillary electrophoresis in the frontal analysis mode (CE/FA), as promising technique for assessment of drug-protein interaction was used. The free drug concentration was measured from height of the frontal peak and calculated based on the external drug standard in absence of protein. With a known concentration of total drug, the percentage of protein bound drug was determined. The binding parameters were also estimated based on the equilibrium dialysis experiment which is considered to be a reference method. This study was designed to examine the interaction of dexamethasone sodium phosphate (DXM) with BSA and HSA under simulated physiological conditions (pH 7.4, 67 mM phosphate buffer, I = 0.17). Using fixed, at physiological level, HSA and BSA concentrations and increasing DXM concentrations, the number of binding sites (n) and binding constant (K(a) ) was calculated from both nonlinear regression fitting and Scatchard Plot. Despite some differences, it can be concluded that the CE/FA is comparable with equilibrium dialysis, but since the first one offers advantages such as low sample consumption, short analysis time, and high separation efficiency, it can be used in high-throughput screening of drug protein binding at the early stage of drug discovery. Interspecies differences in binding of a drug to albumins have been observed and it should be taken into account in interpretation of the results.

Single bout of endurance exercise increases NNMT activity in the liver and MNA concentration in plasma; the role of IL-6.

BACKGROUND: Methylnicotinamide (MNA) displays vasoprotective activity, however, the regulation of the activity of nicotinamide-N-methyltransferase (NNMT), is largely unknown. We analyze a possible involvement of IL-6 in the activation of NNMT-MNA pathway during an endurance exercise. METHODS: FVB, C57Bl/6J IL6(+/+) and C57Bl/6J IL-6(-/-) mice were subjected to the single bout of endurance exercise consisting of 90 min of swimming. Thereafter, exercise-induced changes in NNMT activity in the liver as well as concomitant changes in the concentration of MNA and its further metabolites in plasma were analyzed. RESULTS: In two strains of mice (FVB and C57Bl/6J IL6(+/+)) 90 min of swimming resulted in approximately 2-3 folds increase in NNMT activity (from 0.14 ± 0.03 to 0.421 ± 0.02 pmol/min/mg, p < 0.05 and from 0.2 ± 0.06 to 0.35 ± 0.07 pmol/min/mg, p < 0.01, respectively) and concomitant increase in the plasma concentration of MNA (from 157 ± 15.06 to 230 ± 16.2 ng/ml, p < 0.01, and from 77.05 ± 14.6 ng/ml to 152.55 ± 58.4 ng/ml; p < 0.01, respectively). However, in C57Bl/6J IL-6(-/-) mice 90 min of swimming did not change liver NNMT activity (from 0.25 ± 0.07 to 0.23 ± 0.06 pmol/min/mg), while MNA concentration in plasma rose approximately two-fold (from 65.3 ± 30.9 ng/ml to 124.8 ± 35.8 ng/ml; p < 0.05). CONCLUSIONS: We demonstrated for the first time that NNMT - MNA pathway is activated by a single bout of endurance exercise. Interestingly, exercise-induced activation of NNMT in the liver involves IL-6, while the rise in MNA concentration in plasma was partially IL-6-independent. Taking into the consideration the pharmacological activity of MNA, IL-6-dependent and IL-6-independent activation of NNMT, may contribute to the exercise capacity. The physiological role of NNMT in the exercise warrant further studies.

Binding of 1-[3-(4-tert-butyl-phenoxy)propyl]piperidine, a new non imidazole histamine H3 receptor antagonist to bovine serum albumin.

The degree of binding of a drug to plasma proteins has a significant effect on its distribution, elimination, and pharmacological effect since only the unbound fraction is available for distribution into extra-vascular space. The binding of DL76 (1-[3-(4-tert-butyl-phenoxy)propyl]piperidine) to bovine serum albumin (BSA) was studied in viitro by equilibrium dialysis at 37 degrees C and pH 7.4 over the concentration range of 0.32-317.18 microM and at a physiological protein concentration of 602 microM. Drug concentrations were determined by validated LC/MS/MS method. Nonlinear regression analyses of the data pointed to a single class of binding sites (m = 1) with a dissociation constant of DL76 equal 49.20 microM. Scatchard plot concave-down curve might indicate positive cooperativity, which was confirmed by the Hill plot with the slope higher than one.

LC-MS-MS Method for the Analysis of New Non-Imidazole Histamine H(3) Receptor Antagonist 1-[3-(4-tert-Butylphenoxy)propyl]piperidine in Rat Serum-Application to Pharmacokinetic Studies.

A sensitive and specific liquid chromatography electrospray ionisation-tandem mass spectrometry method for determination of new non-imidazole histamine H(3) receptor antagonist 1-[3-(4-tert-butylphenoxy)propyl]piperidine (DL76) in rat serum has been developed and validated. Chromatography was performed on a XBridge™ C18 analytical column (2.1 × 30 mm, 3.5 µm, Waters, Ireland) with gradient elution using a mobile phase containing acetonitrile and water with an addition of 0.1% of formic acid. Detection was achieved by an Applied Biosystems MDS Sciex (Concord, Ontario, Canada) API 2000 triple quadrupole mass spectrometer. Electrospray ionization (ESI) was used for ion production. The limit of detection in the SRM mode was found to be 0.5 ng mL(-1). The limit of quantification was 1 ng mL(-1). The precision and accuracy for both intra- and inter-day determination of DL76 ranged from 1.65 to 15.09% and from 88.74 to 113.43%. The results of this analytical method validation allow to carry out pharmacokinetic studies in rats. The method was used for the pilot study of the pharmacokinetic behavior of DL76 in rats after intravenous administration.

Application of liquid chromatography-tandem mass spectrometry method for the simultaneous quantitative analysis of propentofylline and its chiral metabolite M1 in rats.

A sensitive and selective liquid chromatographic-electrospray ionization mass spectrometric method for the simultaneous determination of propentofylline and enantiomers of its active metabolite M1 in rat serum, cortex and hippocampus was developed and validated according to GLP procedures. Sample preparations were carried out by liquid-liquid extraction using diethyl ether after the addition of the internal standard (pentoxifylline). The dried residue was reconstituted in mobile phase and injected onto a Chiralpak AD column (10 µm, 250 × 4.6 mm i.d.). The limit of quantification for propentofylline in serum, cortex and hippocampus was set at 0.25 ng/mL and for enantiomers of its metabolite M1 at 1.25 ng/mL. The established LC/ESI-MS/MS method has been successfully applied to an initial pharmacokinetic study of propentofylline and also to assessment of distribution of parent drug and enantiomers of its pharmacologically active metabolite M1 to cortex and hippocampus after intravenous administration of propentofylline to rats at a dose of 5 mg/kg.

Nicotinamide N-methyltransferase (NNMT) and 1-methylnicotinamide (MNA) in experimental hepatitis induced by concanavalin A in the mouse.

Nicotinamide N-methyltransferase (NNMT), which converts nicotinamide (NA) to 1-methylnicotinamide (MNA), is up-regulated in the cirrhotic liver. Because MNA displays PGI(2)-dependent anti-inflammatory effects, the up-regulation of NNMT may play a regulatory role in liver inflammation. In the present work, we analyzed changes in NNMT activity in the liver and concomitant changes in the concentration of endogenous MNA in plasma in T-cell dependent hepatitis induced by concanavalin A (ConA) in BALB/c mice. Furthermore, we tested whether exogenous MNA possessed a protective effect against ConA-induced hepatitis. Development of liver injury induced by ConA (10 mg/kg, iv) was characterized by measurements of plasma concentration of alanine aminotransaminase (ALT), inflammatory cytokines (INF gamma and TNFalpha) and by histopathological examination. ConA-induced hepatitis was characterized by an early activation of inflammatory cytokines (IFN gamma; from below 0.05 ng/ml to 23.72 +/- 8.80 ng/ml; TNFalpha;from 0.07 +/- 0.01 ng/ml to 0.71 +/- 0.12 ng/ml, 2 h after ConA), an elevation of ALT (from 40.65 +/- 3.2 U/l to 5,092.20 +/- 1,129.05 U/l, 8 h after ConA) and by morphological signs of severe liver inflammation and injury (24 h after ConA). In mice injected with ConA, NNMT activity in the liver was up-regulated approximately 2-fold to 3-fold, 8-24 h after ConA injection. The concentration of MNA and its metabolites (Met-2PY and Met-4PY) in plasma were elevated approximately 2-fold 8 h after ConA injection. Exogenous MNA (100 mg/kg, iv) diminished ConA-induced liver injury, and this effect was reversed by an antagonist of the prostacyclin receptor, RO 3244794 (10 mg/kg, po). In conclusion, the present study demonstrated that hepatic NNMT activity and MNA concentration in plasma significantly increased during the progression of ConA-induced hepatitis in mice. This response may play a hepatoprotective role compatible with the PGI(2)-releasing properties of MNA.

Determination of endothelin-1 in rats using a high-performance liquid chromatography coupled to electrospray tandem mass spectrometry.

A sensitive and specific liquid chromatography tandem mass spectrometry method with electrospray ionization for the determination of endothelin-1 in rat plasma and lung effluents has been developed and validated. Detection was achieved by an Applied Biosystems MDS Sciex API 2000 triple quadrupole mass spectrometer coupled to an Agilent 1100 LC system. The limit of detection and the limit of the quantification of ET-1 in matrix buffer was estimated at 40 pM and 1 nM, respectively. The precision and accuracy for both intra- and inter-day determination of the analyte ranged from 2.5% to 14.7% and from 104.2% to 113.3%, respectively. No significant relative matrix effect was observed. Stability of ET-1 established in a bench-top, autosampler, long-term storage stability as well as freeze/thaw cycles shown no significant degradation products in the samples. The results of the method validation indicated that this method is applicable for the determination of the ET-1 concentration in an effluent from the isolated lung preparation as well as in vivo in plasma samples to evaluate ET-1 as a potential biomarker of the progression of pulmonary endothelial dysfunction and pulmonary hypertension in rats induced by a monocrotaline injection.

Simultaneous determination of nicotinic acid and its four metabolites in rat plasma using high performance liquid chromatography with tandem mass spectrometric detection (LC/MS/MS).

A sensitive and specific liquid chromatography electrospray ionization-tandem mass spectrometry method for the simultaneous quantitation of nicotinic acid (NicA) and its metabolites nicotinamide (NA), 1-methylnicotinamide (MNA), 1-methyl-2-pyridone-5-carboxamide (M2PY) and 1-methyl-4-pyridone-5-carboxamide (M4PY) in rat plasma has been developed and validated. As an internal standard, 6-chloronicotinamide was used. The samples (100 microL) were subjected to deproteinization with acetonitrile (200 microL) and then, after centrifugation, 150 microL of the supernatant was transferred into conical vial and evaporated. Dry residue was reconstituted in 100 microL of the ACN/water (10:90, v/v) mixture. Chromatography was performed on a Waters Spherisorb 5 microm CNRP 4.6 x 150 mm analytical column with gradient elution using a mobile phase containing acetonitrile and water with 0.1% of formic acid. The full separation of all compounds was achieved within 15 min of analysis. Detection was performed by an Applied Biosystems MDS Sciex API 2000 triple quadrupole mass spectrometer set at unit resolution. The mass spectrometer was operated in the selected reactions monitoring mode (SRM), monitoring the transition of the protonated molecular ions m/z 153-110 for M2PY, 153-136 for M4PY, 124-80 for NicA, 123-80 for NA and 137-94 for MNA. The mass spectrometric conditions were optimized for each compound by continuously infusing the standard solution at the rate of 5 microL/min using a Harvard infusion pump. Electrospray ionization (ESI) was used for ion production. The instrument was coupled to an Agilent 1100 LC system. The precision and accuracy for both intra- and inter-day determination of all analytes ranged from 1.3% to 13.3% and from 94.43% to 110.88%. No significant matrix effect (ME) was observed. Stability of compounds was established in a battery of stability studies, i.e. bench-top, autosampler and long-term storage stability as well as freeze/thaw cycles. The method proved to be suitable for various applications. In particular using this method we detected increased concentration of MNA and its metabolites in rat plasma after treatment with exogenous MNA (100 mg/kg), as well as increased concentration of endogenous NA and MNA in rat plasma in the early phase of hypertriglyceridemia development in rats fed high-fructose diet.

Validation of a high-performance liquid chromatography method for pharmacokinetic evaluation of pentoxifylline and lisofylline in rat serum and tissues.

The aim of this paper was to validate an analytical method for the simultaneous determination of PTX and its active metabolite (-)-(R)-M1 in rat serum and some tissues using a high-performance liquid chromatography method with ultraviolet detection (HPLC-UV). The specificity, linearity, precision, accuracy, recovery, lower limit of detection, lower limit of quantification and stability study were successively conducted according to GLP procedures. HPLC separation of all compounds was carried out on a normal-phase ChiralPak AD column (250 mm x 4.6 mm i.d., 5 mm), using, as a mobile phase, a mixture of hexane and 2-propanol (84:16, v/v) containing 0.01% of diethylamine with a flow rate of 1.5 mL x min(-1). The calibration curves from all studied matrices were linear across the concentration range from 0.01 to 100 mg x mL(-1) with a lower limit of quantification of 0.01 microg x mL(-1) for all analytes. The application of the assay to a pilot pharmacokinetic study and tissue distribution of the compounds in rats after intraperitoneal dosing of 50 mg x kg(-1) of PTX was described. Significant (p<0.05) differences between serum and tissue levels of PTX, (-)-(R)-M1 and (+)-(S)-M1 were observed.

Pharmacokinetic modelling of pentoxifylline and lisofylline after oral and intravenous administration in mice.

The aim of this study was to develop pharmacokinetic models for pentoxifylline (PTX) and the R(-)-enantiomer of the PTX metabolite 1, lisofylline (LSF), in order to identify some factors influencing the absorption of these compounds from the intestines and to clarify mechanisms involved in their non-linear pharmacokinetics. Serum samples were collected after oral and intravenous administration of PTX and LSF to male CD-1 mice at two different doses. In addition, both compounds under investigation were coadministered with a modulator of drug transporters, verapamil, and an inhibitor of cytochrome P450 (CYP) 3A4, ketoconazole. Pharmacokinetic analysis revealed that a one-compartment model with Michaelis-Menten type absorption and elimination best described the pharmacokinetics of PTX, whereas the LSF concentration-time data were adequately fitted to a two-compartment model with a first-order absorption and Michaelis-Menten type elimination process. Both coadministered compounds significantly decreased the area under the concentration-time curve from 0 to 60 min calculated for PTX and increased the value of this parameter for LSF. The results of this study indirectly suggest that saturation of drug transport across intestinal cells and elimination from the central compartment may be responsible for the non-linear pharmacokinetics of PTX, whereas in the case of LSF, the dose dependency in the pharmacokinetics is solely related to the elimination from the central compartment. It seems that the observed changes in PTX and LSF concentrations after coadministration with verapamil and ketoconazole may be clinically significant, especially after chronic treatment, however further studies are necessary to assess the importance of these interactions in humans.

Application of liquid chromatography-tandem mass spectrometry method for the analysis of new nonselective beta-adrenergic blocker 1-(1-H-indol-4-yloxy)-3-{[2-(2-methoxy phenoxy)ethylo]amino}propan-2-ol (2F109) in rat plasma.

A sensitive and specific liquid chromatography electrospray ionization-tandem mass spectrometry method for the enantioselective determination of the novel beta-adrenolytic compound, 1-(1-H-indol-4-yloxy)-3-{[2-(2-methoxyphenoxy)ethylo]amino} propan-2-ol, in rat plasma has been developed and validated. Chromatography was performed on a reversed-phase Chiralcel OD-RH analytical column (150x4.6 mm, 5 microm, Daicel Chemical Industries, Tokyo, Japan) with isocratic elution using a mobile phase containing acetonitrile and water with 0.01% formic acid. Detection was achieved by an Applied Biosystems MDS Sciex (Concord, Ontario, Canada) API 2000 triple quadrupole mass spectrometer. Electrospray ionization (ESI) was used for ion production. The limit of detection in the MRM mode was found to be 1.25 ng/ml. The limit of quantification of both enantiomers was 2.5 ng/ml. The precision and accuracy for both intra- and inter-day determination of 2F109 enantiomers ranged from 2.6 to 12% and from 89.1 to 107.1%. This analytical method allowed us to carry out pharmacokinetic studies in rats. Our findings demonstrate that 2F109 shows stereoselective disposition in rat plasma after i.v. administration. The terminal half-lives of (+)-(R)-2F109 and (-)-(S)-2F109 were 33.5 and 42.6 min, respectively. The AUC0-inf of (+)-(R)-2F109 exceeded that of (-)-(S)-2F109.

Immobility stress induces depression-like behavior in the forced swim test in mice: effect of magnesium and imipramine.

Previously, we demonstrated antidepressant-like effect of magnesium (Mg) in the forced swim test (FST). Moreover, the joint administration of Mg and imipramine (IMI) at ineffective doses per se, resulted in a potent reduction in the immobility time in this test. In the present study, we examined the effect of immobility stress (IS), and Mg and/or IMI administration on FST behavior. IS induced enhancement of immobility time, which was reversed by Mg or IMI at doses ineffective in non-stressed mice (10 mg/kg and 15 mg/kg, respectively). The joint administration of Mg and IMI was effective in both IS and non-stressed animals in FST. IS did not significantly alter locomotor activity, while IMI or Mg + IMI treatment in IS mice reduced this activity. We also measured serum and brain Mg, IMI and its metabolite desipramine (DMI) concentration in mice subjected to FST and injected with Mg + IMI, both restrained and non-restrained. In the present study we demonstrated a significant increase (by 68%) in the brain IMI and a slight, non-significant reduction in DMI concentration in IS + Mg + IMI + FST vs. Mg + IMI + FST groups, which might indicate the reduction in brain IMI metabolism. The IS-induced reduction in brain IMI metabolism did not participate in the activity in FST, since no differences in such activity were noticed between IS + Mg + IMI + FST and Mg + IMI + FST groups. The present data suggest that IS-induced increase in immobility time in FST is more sensitive for detection antidepressant-like activity. However, further studies are needed to examine the effect of other antidepressants in such an experimental paradigm.

Nebulized pentoxifylline for prevention of bronchopulmonary dysplasia in very low birth weight infants: a pilot clinical study.

OBJECTIVE: To evaluate the effectiveness of nebulized pentoxifylline (PTXF) compared to intravenous dexamethasone (DX) or placebo (nebulized distilled water) for the prevention of bronchopulmonary dysplasia (BPD). METHODS: One hundred and fifty very low birth weight infants were randomly assigned to three groups. Entry criteria were the need for oxygen administration on the fourth day of life, irrespective of whether ventilatory support was required. PTXF was administered with a nebulizer every 6 hours on three consecutive days (a single course) in a dose of 20 mg/kg when infants were breathing spontaneously or 10 mg/kg when they needed ventilatory support. DX was given every 12 hours on three consecutive days in a dose of 0.25 mg/kg. Nebulized distilled water was administered with the schedule of inhalation as in the PTXF group. When the need for ventilatory support or oxygen dependency persisted, the course of both drugs and placebo administration was repeated every seven days until the diagnosis of BPD was established. RESULTS: Both PTXF and DX reduced the incidence of disease when compared with placebo. The respective data obtained for the PTXF-group versus the placebo group were as follows: difference in risk, 27%; OR: 0.32; CI: 0.11-0.94; p = 0.039; whereas the results for the DX-group versus the placebo group were: difference in risk, - 23%; OR: 0.39; CI: 0.14-1.14; p = 0.07. CONCLUSION: Our data show that nebulized PTXF reduces the risk of BPD and may be a potential alternative to steroids in the prevention of this disease.

Interconversion and tissue distribution of pentoxifylline and lisofylline in mice.

The aim of this study was to assess the interconversion pharmacokinetics and tissue distribution of pentoxifylline and the active (R)-enantiomer of its metabolite M1, lisofylline in male CD-1 mice. Both compounds were administered intravenously at a dose of 50 mg/kg on two separate occasions. Serum and tissues were collected at different time points following drug administration. In addition, the (S)-enantiomer of M1 was administered to a group of mice and serum samples were obtained. Analyte concentrations were measured by chiral HPLC. All serum concentration versus time data were fitted simultaneously to a pharmacokinetic model incorporating interconversion processes of parent drug and metabolites. The estimated conversion clearance of (-)-(R)-M1 to pentoxifylline (CL21) was six times greater than that for the reverse process (CL12). The interconversion of pentoxifylline and (+)-(S)-M1 was faster as reflected by the values of conversion clearances CL13 and CL31 which were approximately 16 and 7 times greater in comparison with the corresponding clearances for the interconversion of pentoxifylline and (-)-(R)-M1. When fitting pharmacokinetic data of both parent compounds to a one-compartment model, the values of elimination clearances assessed were close to those obtained on the basis of the interconversion model. After administration of pentoxifylline, tissue-to-serum AUC ratios ranged from 0.1 for liver and lungs to 0.32 for brain tissue. Serum levels of its metabolite, (-)-(R)-M1 were very low, whereas its tissue levels exceeded serum concentrations. The highest value of metabolite-to-parent AUC ratio (4.98) was observed in lungs. When (-)-(R)-M1 was given as a parent drug, tissue-to-serum AUC ratios in liver, kidney, and lungs were very close and ranged from 0.64 to 0.72. At the same time, levels of its metabolite, pentoxifylline were relatively low both in serum and all tissues studied. In consequence, metabolite-to-parent AUC ratios did not exceed the value of 0.27. In conclusion, reversible metabolism plays a modest role in the disposition of pentoxifylline and (-)-(R)-M1. It seems that pentoxifylline has less favourable pharmacokinetic properties than (-)-(R)-M1 due to lower concentrations attained in target organs. High levels of (-)-(R)-M1 observed after pentoxifylline administration in certain tissues such as liver or lungs suggest that pentoxifylline may constitute an effective prodrug for (-)-(R)-M1 in these organs.

Enhancement of antidepressant-like activity by joint administration of imipramine and magnesium in the forced swim test: Behavioral and pharmacokinetic studies in mice.

The effect of joint administration of imipramine (IMI) and magnesium (Mg) on antidepressant-like activity was studied in mice using forced swim test (FST). Mg doses ineffective per se (5 and 10 mg/kg) given jointly with IMI also at ineffective doses (10 and 15 mg/kg) resulted in a potent reduction in the immobility time. Since these combined treatments did not influence locomotor activity, the antidepressant-like activity was not due to non-specific behavioral activation. Moreover, we estimated the effect of joint administration of magnesium and IMI in FST on serum and brain magnesium, IMI and its active metabolite desipramine (DMI) concentrations in mice. Swim stress (mice subjected to FST) increased the magnesium concentration in serum and decreased it in the brain compared to naive animals. Moreover administration of IMI increased (normalized) magnesium brain concentration, without influence on the serum level. Joint administration of IMI and magnesium did not influence magnesium (compared with FST) or IMI and DMI (compared with IMI treatment alone) concentrations in both examined tissues. The present data demonstrated an enhancement of the antidepressant-like effect by joint administration of IMI and magnesium in the FST, and further indicate the particular role of magnesium in the antidepressant action. Since there was no increase in IMI, DMI or magnesium concentration after joint administration of magnesium and IMI, the data suggest that pharmacodynamic rather than pharmacokinetic interaction between magnesium and IMI is accountable for behavioral effect in the FST.

Pharmacokinetic interaction after joint administration of zinc and imipramine in forced swim test in mice.

Recent preclinical and clinical data indicate beneficial role of zinc in the antidepressant treatment. To evaluate the mechanism of interaction between zinc and antidepressants, in the present study we examined the brain zinc, imipramine and desipramine concentrations in mice treated with combinations of zinc and imipramine and subjected to the forced swim test. We have chosen doses of zinc (10 mg/kg) and imipramine (15 mg/kg) which we have previously found to be ineffective in the forced swim test when given alone. However, when administered jointly, a significant reduction in the immobility time in this test was demonstrated. In the present study, we demonstrated a significant ca. 60% reduction in the brain desipramine and non-significant reduction (ca. 40%) in brain imipramine concentrations in the group of animals treated with zinc plus imipramine compared with animals treated with imipramine alone. The brain zinc concentration in the zinc plus imipramine group was reduced when compared with the group treated with zinc or imipramine alone. Since there was no increase in brain imipramine/desipramine or zinc brain concentration after combined zinc and imipramine treatment, the data suggest that pharmacodynamic rather than pharmacokinetic interaction between zinc and imipramine is responsible for behavioral effect in the forced swim test.

Recent applications of stereoselective chromatography.

Some recent applications of stereoselective chromatography in the fields of clinical pharmacy, drug analysis, food, and natural products are reviewed. The review is documented with up-to-date literature, which will assist further expansion of research in these areas.