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A M Taburet

Publications and source records attributed to A M Taburet.

At least 19 recordsLinked to original sources
PubMed2005

Population pharmacokinetic analysis for nelfinavir and its metabolite M8 in virologically controlled HIV-infected patients on HAART.

AIMS: To describe the pharmacokinetics of nelfinavir and its main metabolite M8 in HIV-infected patients with a sustained virological response, to characterize the effect of covariates and to estimate inter- and intra-individual variability in the pharmacokinetics. METHODS: Three hundred and twenty concentrations of both nelfinavir and M8 were measured in 46 patients enrolled in the COPHAR 1-ANRS 102 study. Blood samples were taken at a first visit (one sample before drug administration and four samples at fixed times after) and at a second visit 1 to 3 months later (one before and one 3 h after drug administration). The data from both visits on nelfinavir and M8 were modelled jointly in all patients using a population approach. RESULTS: A one-compartment model with first-order absorption and elimination best described nelfinavir data, with an additional compartment incorporating a first order rate-constant describing the metabolism of the drug to M8. For nelfinavir, the apparent volume of distribution (V/F ) (95% confidence interval for the mean), was 309 l (185, 516), the absorption rate constant (k(a)) was 0.4 h(-1) (0.2, 0.8), and the apparent clearance (CL/F ) was 37.3 l h(-1) (32, 44). For M8, V(m) /(Fk(m)) and CL(m)/(Fk(m)) were 866 l h(-1) (351, 2161) and 1670 l (965, 2894), respectively. The interindividual variabilities were 34.9%, 34.3% and 62.2% for V/F, CL/F and CL(m)/(Fk(m)), respectively. The interoccasion variability was 27.8% for CL/F. The mean half-lives were 05.38 h and 00.44 h for nelfinavir and M8, respectively. Significant but opposite effects of comedication with zidovudine were found on nelfinavir CL/F and M8 CL(m)/(Fk(m)), but they were not considered to be clinically relevant. CONCLUSIONS: A joint model was found to describe adequately nelfinavir and M8 concentrations and was used to estimate pharmacokinetic parameters for M8. The model can be used to build reference pharmacokinetic profiles for therapeutic drug monitoring of the drug.

Adult↗
PubMed2002

In vitro effects of tacrolimus on human cytochrome P450.

Tacrolimus, a potent immunosuppressive drug, is known to be metabolized predominantly in the liver by cytochrome P450 3A (CYP3A). In order to determine the potential of tacrolimus to inhibit the metabolism of other drugs, we have investigated its inhibitory effects on specific cytochrome reactions. Specific substrates for the seven cytochromes (CYPs) 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4/5 were incubated with human hepatic microsome preparations with or without specific inhibitors or tacrolimus and the metabolites were detected by high-pressure liquid chromatography (HPLC) or fluorimetric methods. All the specific inhibitors reduced or abolished the specific CYP activity. Tacrolimus had no effect on any CYP at concentrations below 1 microM, while at higher concentrations it had a mild inhibitory effect on CYP3A4 and 3A5. These observations suggest that tacrolimus is unlikely to potentiate the effect of coadministered drugs through inhibition of their metabolism in the liver.

Aryl Hydrocarbon Hydroxylases↗
PubMed2002

Single-dose pharmacokinetics of amprenavir coadministered with grapefruit juice.

In this crossover study in 12 healthy volunteers, coadministration of amprenavir (1,200 mg; single dose) with grapefruit juice slightly reduced the maximum concentration of drug in serum (Cmax) compared to administration with water (7.11 versus 9.10 microg/ml), slightly increased the time to Cmax (1.13 versus 0.75 h), and did not affect the area under the concentration-time curve from 0 to 12 h (AUC(0-12)), the AUC(0-infinity), or the concentration at 12 h. Therefore, grapefruit juice does not clinically significantly affect amprenavir pharmacokinetics.

Administration, Oral↗
PubMed2000

Simultaneous high-performance liquid chromatographic determination of the antiretroviral agents amprenavir, nelfinavir, ritonavir, saquinavir, delavirdine and efavirenz in human plasma.

This article describes a method for the simultaneous determination of four licensed HIV protease inhibitors (amprenavir, nelfinavir, saquinavir and ritonavir) and two novel non-nucleoside reverse transcriptase inhibitors (efavirenz and delavirdine) in human plasma in a single run. Plasma samples (500 microl) were treated by liquid-liquid extraction with methyl tert.-butyl ether. The compounds were separated by reversed-phase liquid chromatography on a C(18) column with spectrophotometric detection at 260 nm. The method is linear over the specific ranges investigated, accurate (inaccuracy <11.7%) and showed intra-day and inter-day precision within the ranges of 0.9-7.0 and 1.9-8.8%, respectively. The six compounds were stable in plasma after 6 months of storage at -20 degrees C and after five freeze-thaw cycles.

Anti-HIV Agents↗
PubMed2000

Conversion from cyclosporin A to tacrolimus in pediatric liver transplantation.

The dosing regimen for conversion from cyclosporin A (CsA) to tacrolimus immunosuppression was studied in 12 pediatric liver allograft recipients. Patients were stratified according to their age. Tacrolimus was started orally at a dosage of 0.05 mg/kg b.i.d., 12 h after stopping CsA administration and increased thereafter if needed. Tacrolimus and CsA concentrations were assayed by immunoassay using, respectively, an IMx and a TDx autoanalyzer (Abbott-France). Mean CsA concentration was in the therapeutic range 12 h prior to and at the time of introduction of tacrolimus. After 72 h of tacrolimus therapy, CsA concentrations were undetectable whereas mean tacrolimus concentration was 10.4 ng/mL with a mean dose of 0.09 mg/ kg b.i.d. The decline of CsA concentration was clearly biphasic. A slower decline in CsA concentration was detected after initiation of tacrolimus therapy, suggesting an inhibition of CsA metabolism by tacrolimus. No nephrotoxicity was observed. This dosage regimen allowed effective immunosuppression while avoiding additive nephrotoxicity.

Adolescent↗
PubMed1999

In vitro effects of racemates, separate enantiomers and major metabolites of mefloquine and halofantrine on metoprolol biotransformation by rat liver microsomes.

1. The effects of the anti-malarial drugs mefloquine and halofantrine and of their major metabolites on metoprolol metabolism by rat liver microsomes have been investigated. 2. The observed Km and Vmax, and the formation kinetics of alpha-hydroxymetoprolol and O-demethylmetoprolol, two major metoprolol metabolites, were in keeping with published data. 3. In vitro, mefloquine competitively inhibited metoprolol biotransformation, whereas halofantrine did so in a mixed fashion. The mefloquine Ki of metoprolol alpha-hydroxylation and O-demethylation were 3.4 and 5.8 microM respectively, whereas those of halofantrine were 0.15 and 0.32 microM respectively. 4. The main metabolites, N-debutylhalofantrine and carboxymefloquine, were 4-10-fold less inhibitory than the parent drugs. The difference in inhibitory potency of parent drugs and metabolites was higher for halofantrine than for mefloquine. The potency order for metoprolol metabolism inhibition was halofantrine >> mefloquine = N-debutylhalofantrine > carboxymefloquine. 5. A preliminary study with anti-malarial enantiomers showed a weak difference, in metoprolol metabolism inhibition between the enantiomers of halofantrine or mefloquine. 6. It is concluded that halofantrine is a potent inhibitor of metoprolol metabolism and that halofantrine metabolites or its enantiomers may have a different inhibitor potency than the parent drug: (1) the inhibition potency of these compounds should be studied in vitro and (2) their in vivo elimination half-life and plasma concentrations should be taken into be account to extrapolate this experimental results to in vivo.

Animals↗
PubMed1999

Halofantrine metabolism in microsomes in man: major role of CYP 3A4 and CYP 3A5.

We have clarified the contribution of the different enzymes involved in the N-debutylation of halofantrine in liver microsomes in man. The effect of ketoconazole and cytochrome P450 (CYP) 3A substrates on halofantrine metabolism has also been studied. The antimalarial drug halofantrine is metabolized into one major metabolite, N-debutylhalofantrine. In microsomes from nine livers from man, N-debutylation of halofantrine was highly variable with apparent Michaelis-Menten constant V(max) and K(m) values of 215+/-172 pmol min(-1) mg(-1) and 48+/-26 micromol L(-1), respectively, (mean+/-standard deviation). Formation of N-debutylhalofantrine was cytochrome P450 (CYP)-mediated. Studies using selective inhibitors of individual CYPs revealed the role of CYP 3As in the formation of N-debutylhalofantrine. alpha-Naphthoflavone, a CYP 3A activator, increased metabolite formation. In microsomes from 12 livers from man the rate of N-debutylation of halofantrine correlated strongly with CYP 3A4 relative levels (P = 0.002) and less strongly, but significantly, with CYP 2C8 levels (P = 0.025). To characterize CYP-mediated metabolism of halofantrine further, incubations were performed with yeast microsomes expressing specific CYP 3A4, CYP 3A5, CYP 2D6, CYP 2C8 and CYP 2C19 from man. The rate of formation of N-debutylhalofantrine was six- and twelvefold with CYP 3A4 than with CYP 3A5 and CYP 2C8, respectively. CYP 2D6 and CYP 2C19 did not mediate the N-debutylation of halofantrine, but, because in-vivo CYP 2C8 is present at lower concentrations than CYP 3A in the liver in man, the involvement of CYP 3As would be predominant. Diltiazem, erythromycin, nifedipine and cyclosporin (CYP 3A substrates) inhibited halofantrine metabolism. Similarly, ketoconazole inhibited, non-competitively, formation of N-debutylhalofantrine with an inhibition constant, K(i), of 0.05 microM. The theoretical percentage inhibition of halofantrine metabolism in-vivo by ketoconazole was estimated to be 99%. These results indicate that both CYP 3A4 and CYP 3A5 metabolize halofantrine, with major involvement of CYP 3A4. In-vivo, the other CYPs have a minor role only. Moreover, strong inhibition, and consequently increased halofantrine cardiotoxicity, might occur with the association of ketoconazole or other CYP 3A4 substrates.

Aryl Hydrocarbon Hydroxylases↗
PubMed1999

Glucuronidation of drugs by hepatic microsomes derived from healthy and cirrhotic human livers.

Pharmacokinetic studies demonstrated that the decrease in drug biotransformation in hepatic failure depends on the metabolic pathways involved. To test whether glucuronidation reactions supported by UDP-glucuronosyltransferases are differentially affected in such conditions, we investigated the in vitro glucuronidation of four selected drugs and xenobiotics (zidovudine, oxazepam, lamotrigine, and umbelliferone) by using microsomes from human healthy and unhealthy (cirrhosis, hepatitis) livers as enzyme sources. Theses substances are glucuronidated by several UDP-glucuronosyltransferase isoforms. Lidocaine N-deethylation activity measured concomitantly was used as a positive control, because the inhibition of this reaction in patients with hepatic diseases is well documented. The metabolic clearances of zidovudine and lidocaine were decreased significantly in liver cirrhosis (0.17 versus 0.37 microliter/min/mg protein and 0.40 versus 2.73 microliter/min/mg protein, respectively) as a consequence of a decrease of their corresponding Vmax of metabolism. By contrast, the metabolic clearances of oxazepam, umbelliferone, and lamotrigine glucuronidation remained unchanged. Previous studies reported that the in vivo oral clearances of zidovudine and lidocaine were decreased by 70% and 60%, respectively, in cirrhotic livers, whereas those of lamotrigine and oxazepam were not affected. Consequently, it is likely that the in vitro metabolic data, which support the in vivo results, therefore could contribute to reasonably predict the level of impairment of hepatic clearance in patients with liver cirrhosis.

Adolescent↗
PubMed1999

Effect of selected antimalarial drugs and inhibitors of cytochrome P-450 3A4 on halofantrine metabolism by human liver microsomes.

Halofantrine (HF) is used in the treatment of uncomplicated multidrug-resistant Plasmodium falciparum malaria. Severe cardiotoxicity has been reported to be correlated with high plasma concentrations of HF but not with that of its metabolite N-debutylhalofantrine. The aim of this study was to investigate the effects of other antimalarial drugs and of ketoconazole, a typical cytochrome P-450 3A4 inhibitor, on HF metabolism by human liver microsomes. Antimalarial drug inhibitory effects were ranked as follows: primaquine > proguanil > mefloquine > quinine > quinidine > artemether > amodiaquine. Artemisine, doxycycline, sulfadoxine, and pyrimethamine showed little or no inhibition of HF metabolism. Mefloquine, quinine, quinidine, and ketoconazole used at maximal plasma concentrations inhibited N-debutylhalofantrine formation noncompetitively with Ki values of 70 microM, 49 microM, 62 microM, and 0.05 microM resulting in 7%, 49%, 26%, and 99% inhibition, respectively, in HF metabolism. In conclusion, we showed that quinine and quinidine coadministered with HF might inhibit its metabolism resulting in the potentiation of HF-induced cardiotoxicity in patients. This requires a close monitoring of ECG. For the same reasons, the concomitant administration of HF and ketoconazole must be avoided. By contrast, none of the other antimalarials studied inhibited HF metabolism and, by extrapolation, cytochrome P-450 3A4 activity.

Adolescent↗
PubMed1996

Drug interactions with antiviral drugs.

Antiviral drug interactions are a particular problem among immuno-compromised patients because these patients are often receiving multiple different drugs, i.e. antiretroviral drugs and drugs effective against herpesvirus. The combination of zidovudine and other antiretroviral drugs with different adverse event profiles, such as didanosine, zalcitabine and lamivudine, appears to be well tolerated and no relevant pharmacokinetic interactions have been detected. The adverse effects of didanosine and zalcitabine (i.e. peripheral neuropathy and pancreatitis) should be taken into account when administering these drugs with other drugs with the same tolerability profile. Coadministration of zidovudine and ganciclovir should be avoided because of the high rate of haematological intolerance. In contrast, zidovudine and foscarnet have synergistic effect and no pharmacokinetic interaction has been detected. No major change in zidovudine pharmacokinetics was seen when the drug was combined with aciclovir, famciclovir or interferons. However, concomitant use of zidovudine and ribavirin is not advised. Although no pharmacokinetic interaction was documented when didanosine was first administered with intravenous ganciclovir, recent studies have shown that concentration of didanosine are increased by 50% or more when coadministered with intravenous or oral ganciclovir. The mechanism of this interaction has not been elucidated. Lack of pharmacokinetic interaction was demonstrated between foscarnet and didanosine or ganciclovir. Clinical trials have shown that zidovudine can be administered safely with paracetamol (acetaminophen), nonsteroidal anti-inflammatory drugs, oxazepam or codeine. Inhibition of zidovudine glucuronidation has been demonstrated with fluconazole, atovaquone, valproic acid (valproate sodium), methadone, probenecid and inosine pranobex; however, the clinical consequences of this have not been fully investigated. No interaction has been demonstrated with didanosine per se but care should be taken of interaction with the high pH buffer included in the tablet formulation. Drugs that need an acidic pH for absorption (ketoconazole, itraconazole but not fluconazole, dapsone, pyrimethamine) or those that can be chelated by the ions of the buffer (quinolones and tetracyclines) should be administered 2 hours before or 6 hours after didanosine. Very few interaction studies have been undertaken with other antiviral drugs. Coadministration of zalcitabine with the antacid 'Maalox' results in a reduction of its absorption. Dapsone does not influence the disposition of zalcitabine. Cotrimoxazole (trimethoprim-sulfamethoxazole) causes an increase in lamivudine concentrations by 43%. Saquinavir, delavirdine and atevirdine appeared to be metabolised by cytochrome P450 and interactions with enzyme inducers or inhibitors could be anticipated. Some studies showed that interferons can reduce drug metabolism but only a few studies have evaluated the pathways involved. Further studies are required to better understand the clinical consequences of drug interactions with antiviral drugs. Drug-drug interactions should be considered in addition to individual drug clinical benefits and safety profiles.

Antiviral Agents↗
PubMed1995

Pharmacokinetic comparison of oral and local action transcutaneous flurbiprofen in healthy volunteers.

Flurbiprofen is a propionic acid-derived non-steroidal anti-inflammatory drug (NSAID) used widely in the treatment of rheumatism and non-arthritic pain. The pharmacokinetics of topically and orally administered flurbiprofen were compared in a two-part, open study involving healthy adult volunteers. In the first (cross-over) part of the study, 12 Caucasians were randomized to receive either a single oral dose of 50 mg flurbiprofen or a single topical application of a novel 40 mg flurbiprofen-containing patch on the right wrist for 12 h. In the second part of the study, each subject applied a flurbiprofen-containing patch twice daily to the same wrist for 7 days. Plasma concentrations of flurbiprofen and urinary concentrations of the NSAID and its metabolites were measured by high-performance liquid chromatography assay, to enable comparison of the pharmacokinetic parameters for delivery of the drug by both routes. Maximum concentrations of the NSAID in plasma (Cmax) were much lower after a single application of the topical 40 mg flurbiprofen patch than after a single oral dose of 50 mg of the NSAID (mean +/- SD: 43 +/- 16 ng/ml versus 5999 +/- 1300 ng/ml, respectively). After repeated application of the topical patch, Cmax increased only slightly to 103 +/- 57 ng/ml. The mean relative bioavailability of flurbiprofen from the patch was 3.5 +/- 1.7%, calculated from plasma area under the curve data and 4.4 +/- 2.8% from urinary excretion data.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗