Biomedical subjects
Publications and source records attributed to A M Taburet.
The 13C chemical shifts for all the carbon atoms is spironolactone have been assigned. Assignments for nine additional steroids which include the C-7 beta isomer of spironolactone, its C-7 thiol hydrolysis product, the 7 alpha-thioacetate derivative of testosterone and its thiol hydrolysis product are also reported.
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We propose a method in which tracer amounts of a radiolabeled compound are used as the internal standard for the same unlabeled compound in high-performance liquid chromatography. The approach is valuable when a response from the internal standard becomes undesirable due to the presence of interference by the metabolites. We tested our approach with phenacetin and its metabolites, acetaminophen, 2-hydroxyphenacetin, N-hydroxyphenacetin, phenetidine, acetaminophen sulfate conjugate and acetaminophen glucuronide conjugate in biological fluids with the use of [14C]phenacetin and [3H]acetaminophen as the internal standards, and were able to quantitate both phenacetin and acetaminophen simultaneously. We also tested the alternative approach in which the unlabeled drug was used as internal standard for tracer amounts of the same radiolabeled compound, with phenacetin and acetaminophen as the internal standards for tracer amounts of [14C]phenacetin and [3H]acetaminophen. Again, we were able to quantitate the two tracer radiolabeled compounds simultaneously.
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The pharmacokinetics of sodium 2-n-propyl-pentanoate have been studied in pig and human. The drug is excreted in the human urine as a mixture of glucuronide and other unidentified conjugates. It appears that no other conjugates can be found in pig's urine. Treatment with sulfatase does not identify sulfate-conjugates in human urine. Coadministration of acetyl salicylic acid (ASA) increases the fraction of glucuronide and other conjugates in human urine. The rate of renal excretion of the drug appears to be increased during concomitant administration of ASA.
The pharmacokinetics of intravenous and oral tacrolimus was assessed in paediatric liver transplant patients at two centers in Europe. Sixteen patients, age 0.7 to 13 years, participated in the study; 12 patients were evaluable for intravenous pharmacokinetics, and 16 for oral. Intravenous tacrolimus was given as a continuous 24 h infusion (mean 0.037+/-0.013 mg/kg/day), and oral tacrolimus was given in 2 doses per day (mean 0.152+/-0.015 mg/kg). Whole blood samples for the intravenous pharmacokinetic profile were taken before initiation of the first infusion, 4, 8, 12 and 24 h post-infusion, and every 24 h thereafter until intravenous administration was discontinued. During the 12 h wash-out period between intravenous and oral administration, samples were taken every 3 h. Samples for the oral pharmacokinetic profile were taken immediately before the first oral dose and 0.5, 0.75, 1, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-administration. Non-compartmental procedures were used to characterise the pharmacokinetic parameters. Mean estimates for clearance and terminal half-life were 2.3+/-1.2 ml/min/kg and 11.5+/-3.8 h, respectively, following intravenous tacrolimus. The mean bioavailability of oral tacrolimus was 25+/-20%. A strong correlation was observed between AUC and trough whole blood levels of tacrolimus (r=0.90). The clearance was approximately 2-fold higher than that previously observed in adults; this could explain the higher dosage requirements in children.
A tablet form of nifedipine was given to eight hypertensive hospitalized men (Stage I or II WHO, 45 +/- 10 years old). After an initial placebo test, 20, 40, and 60 mg of nifedipine were given at 8.00 a.m. in random order at 72-hour intervals in a single administration double-blind crossover study. Blood pressure and heart rate were measured twice by the same observer every 20 minutes from 7.00 a.m. to 8.00 a.m. and then hourly until 8.00 p.m., first with the patients recumbent and again after 1 minute of standing. Plasma nifedipine levels were assayed in samples drawn hourly from 8.00 a.m. to noon, every 2 hours from noon to 8.00 p.m., and at 24 and 48 hours after drug ingestion. The three doses all lowered blood pressure significantly. The reduction during recumbency was significantly larger (-18%) and lasted longer (12 hours) after 60 mg than after 20 mg (-11% at 7 hours). The three doses caused similar increases in heart rate (+29% to +38%), the maximum occurring at the second hour and lasting for 5 hours. The peak plasma concentrations and areas under the plasma concentration time curve were dose-dependent; kinetics were linear between 20 and 60 mg, and the half-life of nifedipine tablets was close to 10 hours. The decrease in mean arterial blood pressure correlated strongly with plasma nifedipine levels (r = 0.61; n = 190; p less than 0.001). Four patients experienced mild side effects (headaches, flushes, drowsiness, or weakness). The tablet form of nifedipine had a potent antihypertensive action that lasted longer than that of the capsule formulation.
Concomitant administration of three or more antiretroviral drugs is the standard treatment for HIV-infected patients. I.p. and NNRT are metabolized by cytochrome P450 and are inhibitors or inducers of CYP3A4. Therefore a number of drug-drug interactions are likely to occur. Ritonavir, a potent CYP3A4 inhibitor, is coadministered with saquinavir, indinavir and amprenavir to enhance their plasma concentrations and their virological efficacy. In contrast, nevirapine and efavirenz are CYP3A4 inducers, which warrant an increase in i.p. dosing. These properties lead to interactions with other drugs metabolized by CYP3A4 and a knowledge or the route of biotransformation is useful to avoid side-effects or decrease efficacy (as in the case of statine coadministration). Some important interactions can lead to contraindications such as coadministration of rifampicine, astemizole, ergot derivates or cizapride, as a large decrease or increase in concentration can lead to inefficacy or to major side-effects. Clinical trials and notification of side-effects are important to detect unpredictable interactions and to propose guidelines; such an example is therapeutic drug monitoring of methadone to avoid withdrawal syndrome when coadministered with ritonavir or nelfinavir.
Pharmacokinetics of zidovudine was investigated after oral administration (200 mg) in 25 HIV seronegative subjects: 14 patients with severe renal impairment (creatinine clearance 6 to 31 ml/min), 5 hemodialyzed anuric patients, and 6 healthy subjects. In healthy subjects, G. AZT concentrations are higher than those of AZT; AUC were 23.7 +/- 1.9 and 5.2 +/- 0.6 mumol.h/l respectively. Formation of G. AZT rate-limits its elimination: G. AZT half-life parallels that of AZT which is around 1 hour. In uremic patients AZT concentrations are moderately increased (AUC = 11.7 +/- 1.1 mumol.h/l), whereas half-life and MRT remains unchanged, despite the decreased renal clearance (16 +/- 2 vs 220 +/- 58 ml/min). In contrast G. AZT concentrations are markedly increased (AUC = 403 +/- 89 mumol.h/l). As a consequence of the decreased renal clearance (27 +/- 3 vs 331 +/- 42 ml/min), elimination is the rate limiting step and half-life is increased (8 +/- 2 vs 0.9 +/- 0.1 h). Contribution of a 4-hour hemodialysis session to AZT elimination appears negligible whereas elimination of G. AZT is enhanced.
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