Biomedical subjects

J Catalin

Publications and source records attributed to J Catalin.

At least 37 records · Page 2Linked to original sources

PubMed1995

Dosage adjustment of high-dose methotrexate using Bayesian estimation: a comparative study of two different concentrations at the end of 8-h infusions.

Bayesian estimation (BE) of pharmacokinetic parameters enables the clinician to adjust the dosage of high-dose methotrexate (HDMTX) to correct the inter- and intraindividual variation of concentrations that are responsible for severe toxicity. In this study of 672 HDMTX infusions, we validated an approach that consisted of reaching as nearly as possible a theoretical concentration of 5.10(-4) M or 10(-3) M at the end of an 8-h infusion by adjusting, when necessary, the dosage at the 6th h. The BE of the clearance was compared with that obtained by maximum likelihood estimation (MLE), which was used as reference. BE performance was evaluated by calculating the bias and precision that indicated an overestimation of clearances obtained by BE compared with the higher clearance of the MLE in the group of patients receiving the higher dose (15 and 37.9%). Linear regression analysis of clearance obtained by BE and MLE showed a correlation (p < 0.0001) in both groups of patients with a closer link in those with the lower dose. However, in current clinical practice the important point is to obtain MTX concentration that is as close as possible to the desired concentration. Adjustments were evaluated by comparing the obtained concentrations with the desired theoretical concentration. There was no bias and precision was satisfactory in both groups of patients (15 and 12%, respectively, for 5.10(-4) M and 10(-3) M). This method makes it possible to limit the inter- and intraindividual variations of concentrations. As a result, severe complications were essentially nonexistent and were never life threatening.

Adolescent↗

PubMed1995

Comparative effects of antifungal agents on zidovudine glucuronidation by human liver microsomes.

Zidovudine (ZDV) is extensively metabolised by the liver to an inactive glucuronide (GZDV). Since ZDV is often administered with antimycotic drugs, we studied the effect of six systemic antifungal agents on the in vitro glucuronidation of ZDV by human liver microsomes. 5-fluorocytosine and itraconazole had no inhibitory effect whereas amphotericine B, ketoconazole, miconazole and fluconazole inhibited in vitro GZDV formation (Ki values were 0.13, 0.08, 0.18 and 1.4 mM respectively).

Amphotericin B↗

PubMed1995

Lack of correlation between pharmacokinetics and efficacy of low dose methotrexate in patients with rheumatoid arthritis.

OBJECTIVE: To determine if the variability in the efficacy of methotrexate (MTX) in rheumatoid arthritis (RA) is correlated with its pharmacokinetics. METHODS: MTX pharmacokinetics was evaluated in 46 patients with RA starting a weekly intramuscular low dose MTX treatment. The patients were divided into 32 responders and 14 nonresponders to MTX according to the clinical response in the 6 months after the pharmacokinetic study. MTX plasma (at T0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12 and 24 h) and urine concentrations were measured with the TDx Abbott fluorescence polarization immunoassay. RESULTS: The MTX dosage, age, sex, RA duration, hepatic and renal functions of responders and nonresponders were not different. No difference was found either in peak concentration, residual 24th hour concentration, area under the curve, total body clearance, renal clearance, and terminal T1/2 life of MTX in responders and nonresponders. Surprisingly, patients with adverse reactions had higher total body and renal MTX clearances than those without side effects during the study. CONCLUSION: These data suggest that plasma MTX measurements are not helpful in defining an optimal treatment regimen.

Adult↗

PubMed1994

Effect of cigarette smoke on hepatic and pulmonary cytochromes P450 in mouse: evidence for CYP2E1 induction in lung.

Pulmonary and liver microsomes of male NMRI mice were used to study the inductive effect of cigarette smoke on various cytochrome P450 isoforms implicated in precarcinogen and premutagen bioactivation. The enzymatic activities catalyzed by CYP1A1, CYP2B, CYP2C, CYP2D, CYP2E1 and CYP3A were induced in liver microsomes. Immunoquantification of lung and liver CYP1A1, 2E1 and 3A demonstrated that 1) CYP1A1 was induced in lung and liver, 2) CYP3A subfamily was induced in liver and not detected in lung, 3) CYP2E1 was slightly induced in liver whereas its pulmonary expression was more largely increased (6.8 fold) than CYP1A1 (2.0 fold). This latter data suggests that CYP2E1, which is known to be expressed in human lung, could actively participate in pulmonary carcinogenesis induced by cigarette smoke.

Animals↗

PubMed1994

Pharmacokinetics of intrapleural recombinant interleukin-2 in immunotherapy for malignant pleural effusion.

BACKGROUND: The authors measured pharmacokinetic parameters before, during, and after immunotherapy by continuous intrapleural infusion of recombinant interleukin-2 (rIL-2) and correlated the resulting data with clinical effects in nine patients with malignant pleural effusion. METHODS: The underlying disease was malignant mesothelioma in five patients and adenocarcinoma in four patients. Continuous intrapleural infusion of rIL-2 was performed for 5 days at 21 x 10(6) IU/m2/day. Maximum tolerated dose previously was determined to be 24 x 10(6) IU/m2/day in a Phase I study. Peak levels, the areas under the concentration curve (AUC), and drug half-lives were measured in pleural fluid and plasma samples collected at 0 (baseline), 12, 24, 48, 72, 96, and 120 hours during infusion and at 2, 6, 8, 32, 44, 56, 80, and 120 hours after the end of infusion. RESULTS: High and prolonged intracavitary drug levels were achieved in all but two patients, with a statistically significant correlation between peak values and AUC. Four patients achieved objective responses according to World Health Organization criteria. Neither of the patients with undetectable rIL-2 levels had response to therapy. Serum rIL-2 levels were low regardless intrapleural levels. Mean AUC was lower in the plasma than in the pleural fluid. CONCLUSIONS: This study demonstrates that continuous intrapleural infusion of rIL-2 is an active method of treatment for malignant pleural effusion. The low serum levels associated with this method greatly improve tolerance. The results also indicate that the concentration and duration of intrapleural rIL-2 levels may depend on the extent of pleural invasion. Additional study is needed to confirm this finding.

Adenocarcinoma↗

PubMed1994

Pharmacokinetics of high-dose methotrexate in adult osteogenic sarcoma.

The pharmacokinetics of 222 infusions of high-dose methotrexate (MTX) with leucovorin rescue were studied in 22 adults with osteosarcoma. To reduce the variability of plasma concentration, we individualized dose regimens using a Bayesian method to reach a concentration of 10(-3) M MTX at the end of an 8-h infusion. The mean concentration observed at the end of the infusion was 1016 +/- 143 mumol/l. The mean dose delivered was 13.2 +/- 2 g/m2. The clearance was 49.1 +/- 11.7 ml min-1 m-2. The decay of the plasma concentration of MTX after completion of the infusion followed a two-compartment model with a t1/2 alpha of 2.66 +/- 0.82 h and a t1/2 beta of 15.69 +/- 8.63 h. The volume of distribution was 0.32 +/- 0.08 l/kg. As compared with previously published data, the interindividual and intraindividual variations in the concentration at the end of the infusion were reduced, with values of 14% and 5.9%-21%, respectively, being obtained. Severe toxicities were avoided, and there were only 3 hematologic and 8 digestive grade 3 side effects and no grade 4 complication. The t1/2 alpha and the MTX plasma concentrations at 23 and 47 h were correlated with renal toxicity (P < 0.001). However, no correlation was found between the pharmacokinetic parameters and other signs of toxicity. There was no significant difference in pharmacokinetics between the toxic and nontoxic groups. In the same manner, the parameters of the group of patients sensitive to MTX were not statistically significant different from those of the group of nonsensitive patients.

Adolescent↗

PubMed1994

Abbott PKS system: a new version for applied pharmacokinetics including Bayesian estimation.

Abbott Laboratories has developed a new software package (Abbottbase pharmacokinetic system or PKS package) that employs the principles of pharmacokinetics to assist clinical pharmacologists and clinicians in designing dosage regimens. This software, which runs on IBM PC compatibles, allows Bayesian estimation of individual pharmacokinetic parameters. The aim of the present study was to validate this new system in routine clinical practice for amikacin (40 intensive care unit patients) and theophylline (20 patients). By using the program one or more times during the treatment (50 cases for amikacin and 46 cases for theophylline), dosing recommendations were obtained in real time for all patients. The predictive performance (bias and precision) was assessed by comparing predicted drug concentrations with those measured 24-48 h after dosage recommendation. In the case of amikacin, precision and bias were computed separately for peak and trough levels. In all cases, no statistically significant bias was observed. Finally, our results demonstrate the accuracy of the program in predicting drug levels for amikacin and theophylline. Consequently, the PKS package is reliable for the choice of optimal dosage regimen for amikacin and theophylline.

Administration, Oral↗

PubMed1994

Predictive performance of two software packages (USC*PACK PC and Abbott PKS system) for the individualization of amikacin dosage in intensive care unit patients.

Many dosing methods (nomogram, pharmacokinetic methods, Bayesian methods) can be used for the individualization of amikacin dosing. Among these methods, it is now well known that the Bayesian method provides a rapid and accurate means for individualizing dosage requirements for patients with diverse pharmacokinetic profiles. However, one problem has not been fully resolved. Should we use population-based parameters reflecting the patient population being monitored or should we used general population parameters? The aim of this study was to answer this question using two widely used software programs (USC*PACK PC and Abbott PKS system) and two different population parameters sets. Predictive performance of these methods was assessed with respect to the prediction of amikacin serum concentrations in intensive care unit (ICU) patients. Our results show that the differences between predicted and measured concentrations were unbiased when the population parameters used were adequate. Precision values were comparable with previously reported values. The predictive performance of the two tested software programs are very comparable in ICU patients. In addition, we demonstrated that performance can be enhanced when using population-based parameters which reflect the patient population being monitored. It is therefore advisable for each user to properly characterize each particular patient population.

Adolescent↗

PubMed1994

Pharmacokinetics of folinic acid and 5-methyltetrahydrofolic metabolite after repeated oral administration of calcium folinate following methotrexate treatment.

The pharmacokinetic profiles of folinic acid (FA) and its active metabolite, 5-methyltetrahydrofolic acid, were studied after oral administration of decreasing doses of calcium folinate during 37 courses of high and intermediate dose methotrexate treatment in 25 lymphoma patients. FA was administered at a dose of 6 x 50 mg in 15 courses, 6 x 25 mg in seven courses, 6 x 15 mg in 10 courses and 6 x 7.5 mg in 5 courses. FA, 5-methyltetrahydrofolic acid, methotrexate and 70H-methotrexate were assayed simultaneously by high performance liquid chromatography. When FA was administered at doses between 50 and 15 mg, maximum concentrations of both the drug and its metabolite were always obtained after 1 to 2 h and remained stable. The same was true for the equilibrium concentration of the two products at doses over 15 mg. These findings suggest saturation of absorption and metabolism of folinic acid at doses over 15 mg.

Administration, Oral↗

PubMed1994

[Hepatic transport of mitoxantrone in relation to multiple resistance].

We have examined the effect of cyclosporin A on transport processes (uptake, efflux, binding) of mitoxantrone in isolated rat liver cells. Accumulation and binding of mitoxantrone was rapid with or without cyclosporin A. The initial uptake was linear over a wide concentration range (1 to 1000 microM). For the first 100 s, the rate of uptake is constant. The uptake clearance ranged from 12.53 +/- 3.9 to 33.77 +/- 15.1 nl.min-cell-1 for different extracellular concentrations of mitoxantrone. Also cyclosporin A did not modified this coefficient. Initial binding of mitoxantrone to cell plasma membrane was estimated and it was modified by different extracellular concentrations of mitoxantrone but not by cyclosporin A. Respectively at 60 seconds it accounted to 79.6% and 81.6% of the total transport. Influx of mitoxantrone was not temperature sensitive. We next examined the efflux of mitoxantrone from cells that were preloaded with drug. Initial efflux was rapid for the first 5 minutes. Cyclosporin A slightly decrease this efflux (7%). The data suggest that the mechanism of uptake of mitoxantrone is passive diffusion and that cyclosporin A a p-glycoprotein 170 inhibitor agent has only a weak effect on efflux.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1993

Inhibitory effects of anticancer drugs on dextromethorphan-O-demethylase activity in human liver microsomes.

The dextromethorphan-O-demethylase activity determined in human liver microsomes was used to screen various anticancer drugs for their ability to inhibit this cytochrome CYP2D6-dependent activity. Competitive inhibition indicates that the drug binds the enzyme and is potentially subjected to a polymorphic metabolism. Among the 13 anticancer drugs tested, 4 compounds caused competitive inhibition of dextromethorphan-O-demethylation: lomustine (Ki = 7.7 microM), doxorubicin (Ki = 75 microM), vinorelbine (Ki = 22 microM), and vinblastine (Ki = 42 microM). The results of these studies indicate that the metabolism of the drugs concerned is possibly altered in poor metabolizers of debrisoquine and requires further investigation to study their specific routes of biotransformation. The metabolism of these drugs probably involves various biotransformation pathways, among which the CYP2D6-dependent route would be of minor importance. A second hypothesis is that these drugs could be inhibitors of the isozyme without being a substrate.

Antineoplastic Agents↗

PubMed1993

Is there an interaction between low doses of corticosteroids and methotrexate in patients with rheumatoid arthritis? A pharmacokinetic study in 33 patients.

A study of methotrexate (MTX) pharmacokinetics with and without prednisolone was performed in 33 patients with rheumatoid arthritis. Ten mg im MTX were given on Day 0; patients were divided into 3 groups of 11 persons: Group 1: no corticosteroid; Group 2: prednisolone 15 mg/day per os from D -3 on; Group 3: patients continuing longterm prednisolone treatment (15 mg/day). Groups 1 and 2 were randomized. MTX plasma concentrations were measured at T 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12 and 24 h using fluorescence polarization immunoassay (TDx Abbott). There was no difference between MTX pharmacokinetics of Groups 1 and 2. Area under the curve (AUC), Cmax and residual concentration at 24th h were higher, while total body and renal MTX clearances were lower in Group 3 vs Groups 1 and 2. Only the differences in AUC and total clearance were significant (p < 0.01 and p < 0.05). Tmax and terminal half-life did not differ. Our data suggest a possible influence of prednisolone on MTX pharmacokinetics in longstanding steroid treated patients. The pharmacological processes that might be involved are discussed.

Adrenal Cortex Hormones↗

PubMed1991

Use of human and animal liver microsomes in drug metabolic studies.

A bank of readily available well-characterized human and animal hepatic microsomal fractions has been established. By using these "in vitro" models, we evidenced large interspecies variabilities for various compounds including digoxin, minaprine and two vincaalkaloïds (navelbine, vinblastine). Therefore, extrapolation from animal to human appeared limited and we focused our interest on human liver microsomes. Enzymatic characteristics of human microsomes from 35 different livers were determined using specific monooxygenase (i.e. erythromycin, aniline, aminopyrin...) and UDP-glucuronosyltransferase substrates (i.e. p-nitrophenol, monodigitoxoside digitoxigenin...). A wide variability was thus ascertained between individual for both phase I and phase II metabolic processes. Microsomal fractions were also shown to be of great interest for assessing the P450 cytochrome isoform(s) involved in the biotransformation of a given drug. For instance, using inhibitory experiments, we showed the implication of P450IID in minaprine metabolism. We also demonstrated that P450IIIA is probably involved in vindesine biotransformation. Drug metabolic interactions between cyclosporin A and macrolides were studied using the same model. These results demonstrating that erythromycin is a much more potent inhibitor of cyclosporin A biotransformation than spiramycin, agree closely with "in vivo" data. In conclusion, liver microsomes are powerful tools in studying: i) interspecies and interindividual variabilities, ii) metabolic drug interactions.

Animals↗

PubMed1988

Direct determination of mitoxantrone and its mono- and dicarboxylic metabolites in plasma and urine by high-performance liquid chromatography.

The simultaneous isolation and determination of mitoxantrone (Novantrone) and its two known metabolites (the mono- and dicarboxylic metabolites) were carried out using a high-performance liquid chromatographic (HPLC) system equipped with an automatic pre-column-switching system that permits drug analysis by direct injection of biological samples. Plasma or urine samples were injected directly on to an enrichment pre-column flushed with methanol-water (5:95, v/v) as the mobile phase. The maximum amount of endogenous water-soluble components was removed from biological samples within 9 min. Drugs specifically adsorbed on the pre-column were back-flushed on to an analytical column (Nucleosil C18, 250 X 4.6 mm I.D.) with 1.6 M ammonium formate buffer (pH 4.0) (2.5% formic acid) containing 20% acetonitrile. Detection was effected at 655 nm. Chromatographic analysis was performed within 12 min. The detection limit of the method was about 4 ng/ml for urine and 10 ng/ml for plasma samples. The precision ranged from 3 to 11% depending on the amount of compound studied. This technique was applied to the monitoring of mitoxantrone in plasma and to the quantification of the unchanged compound and its two metabolites in urine from patients receiving 14 mg/m2 of mitoxantrone by intravenous infusion for 10 min.

Chromatography, High Pressure Liquid↗

PubMed1987

Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate after methotrexate infusions.

Methotrexate was administered by IV infusion, 2g (1.19 +/- 0.05 g/m2) over 24 hours, to a homogeneous group of patients undergoing treatment for breast cancer. Three courses were given at three week intervals. Methotrexate and 7-hydroxy-methotrexate plasma and urine pharmacokinetics were investigated. The average terminal half-lives of methotrexate and 7-hydroxy-methotrexate in plasma were 15.02 and 15.19 hours respectively. The area under concentration-time curve was 723.8 +/- 196.4 microM x h for methotrexate and 598.1 +/- 212.5 microM x h for 7-hydroxy-methotrexate. The total average urinary excretions of methotrexate and 7-hydroxy-methotrexate over a 96 hour period were 52% and 5.4% respectively. Urinary clearance of methotrexate was 3.46 +/- 1.4 1/h. In contrast, urinary excretion of 7-hydroxy-methotrexate was not linear. These results confirm the protein binding of metabolite to serum albumin and may suggest that distribution of 7-hydroxy-methotrexate is different from unchanged drug or that the metabolite can be eliminated by another route, such as bile.

Aged↗

PubMed1984

Assay of methotrexate and 7-hydroxymethotrexate by gradient-elution high-performance liquid chromatography and its application in a high-dose pharmacokinetic study.

A paired-ion high-performance liquid chromatographic method is described for the simultaneous determination of methotrexate (MTX) and its major metabolise, 7-hydroxymethotrexate (7-OH-MTX), in plasma and urine. In addition, this technique permits the separation of other known metabolites of MTX, such as DAMPA and MTX-polyglutamates. After selective extraction on an anion-exchange resin column, both compounds and the internal standard, aminopterin, were separated on a reversed-phase octadecylsilane column with UV-detection at 313 nm. The detection limits for plasma and urine samples were approximately 40 ng/ml (8.8 x 10(-8) M) for MTX and 100 ng/ml (2.1 x 10(-7) M) for 7-OH-MTX. This method was applied in pharmacokinetic studies following 24-h infusion of high-dose MTX in four patients during two successive treatments. After the end of the infusion, the mean apparent half-life for the metabolite was 19.1 h, while that for MTX was 8.8 h. A stepwise increase in the plasma concentrations of both MTX and its metabolite was observed during the second MTX infusion. This increase was reflected in the cumulative urinary excretion of both drug and its metabolite.

Journal Article↗

PubMed1983

High-performance liquid chromatographic analysis of MTX, 7-OH-MTX and MTX derivatives: application to intracellular metabolism in tumor cells (HT 29).

In order to study the intracellular metabolism of Methotrexate (MTX) and the cytotoxicity of the antifolates, a specific paired-ion HPLC method has been developed which permits the simultaneous determination of DAMPA, MTX, 7-OH-MTX, MTX-G1, MTX-G2 and MTX-G3. Cells were incubated with 3H-MTX. The MTX metabolites were extracted, purified on SEP-PAK cartridges and further analysed by high-performance liquid chromatography (HPLC). The stationary phase was constituted by a C18 muBondapak and the mobile phase by 5 mM phosphate buffer (pH 7.4) containing 2.5 mM tetrabutylammonium nitrate. The elution was performed with a linear methanol gradient (20--30%). HPLC fractions were collected and radioactivity evaluated by beta counting (retention times: DAMPA = 12.93 min; MTX = 18.29 min; 7-OH-MTX = 21.13 min; MTX-G1 = 22.69 min; MTX-G2 = 26.81 min; MTX-G3 = 30.61 min). This analytical procedure was applied to separate and characterize multiple forms of MTX polyglutamate derivatives in HT 29, a human adenocarcinoma cell line varying the incubation time (4--18 h) and MTX concentration (0.6--10.6 micrometer). The incorporation process seems to be characteristic of a cell line resistant to MTX. The incorporation were very low and after a 4-h exposure time only 5% of the MTX was converted to polyglutamates. Between 1.6 and 10.6 microM MTX, no difference was observed in the polyglutamization. The defect in the incorporation of the drug and in the metabolization process in vitro could partially explain the failure of the MTX treatment in colorectal cancer.

Adenocarcinoma↗

PubMed1983

In vitro formation of polyglutamyl derivatives of methotrexate and 7-hydroxymethotrexate in human lymphoblastic leukemia cells.

The intracellular synthesis of polyglutamyl derivatives of both methotrexate (4-amino-N-10-methylpteroylglutamic acid) and 7-hydroxymethotrexate, the primary plasma metabolite of methotrexate in humans, was evaluated in a methotrexate-sensitive, acute lymphoblastic leukemia cell line, MOLT 4. These studies were performed using a highly specific ion-pairing high-pressure liquid chromatography method which permits the simultaneous determination of methotrexate, 7-hydroxymethotrexate, and their corresponding polyglutamyl derivatives. When MOLT 4 cells were exposed to 1 microM methotrexate, the monoglutamate attained a steady state after 30 min, and polyglutamyl derivatives having from one to 4 additional glutamyl residues were observed over 4 hr. Four additional metabolites were also detected upon incubation with 1 microM 7-hydroxymethotrexate. On the basis of the retention times for these compounds relative to methotrexate polyglutamyl standards and since these metabolites reverted to 7-hydroxymethotrexate upon treatment with a preparation of hog kidney conjugase, they were identified as polyglutamyl derivatives of 7-hydroxymethotrexate. The identification of 7-hydroxymethotrexate polyglutamyl derivatives in vitro raises the possibility of an important new dimension in the pharmacological action of methotrexate. We investigated the effect of extracellular 7-hydroxymethotrexate on net methotrexate uptake and metabolism when cells were exposed simultaneously to 1 microM [3H]-methotrexate and unlabeled 7-hydroxymethotrexate. A decrease in the levels of both intracellular methotrexate and the corresponding polyglutamyl derivatives was noted for cells treated with 1 or 10 microM 7-hydroxymethotrexate. However, no appreciable effect of 7-hydroxymethotrexate on the amount of polyglutamyl derivatives formed relative to the total intracellular antifolate was noted. These studies show that in MOLT 4 cells (a) both methotrexate and 7-hydroxymethotrexate are rapidly converted to polyglutamyl derivatives, and (b) 7-hydroxymethotrexate interferes with net methotrexate accumulation and metabolism when present simultaneously in the extracellular medium. These results, moreover, suggest a potential role for 7-hydroxymethotrexate in modulating the biochemical effects of methotrexate in vivo.

Cell Line↗