Intranuclear concentration measurements of doxorubicin in living leucocytes from patients treated for a lympho-proliferative disorder.

The accumulation of doxorubicin (DOX) in white blood cells of treated patients has been studied by quantitative microspectrofluorometry. From blood samples of treated patients, leucocyte subpopulations were separated by the gradient method. Emission fluorescence spectra from a microvolume of a single living cell nucleus were analysed in terms of spectral shape and fluorescence yield between free and DNA-bound doxorubicin. With this non-destructive analysis technique, intranuclear doxorubicin concentrations were determined within +/- 10%. Doxorubicin concentrations were measured in patients treated with bolus injection. After an accumulation of DOX in leucocytes during the first 30 min, intranuclear doxorubicin concentration did not vary significantly for 24 h, whereas its concentration in plasma decreased. Despite large differences between patients, monocytes accumulated significantly more doxorubicin than granulocytes or lymphocytes did.

Evaluation of 4-aminopyridine and 3,4-diaminopyridine penetrability into cerebrospinal fluid in anesthetized rats.

4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP) when injected intracisternally to anesthetized rats induced qualitatively similar central nervous system stimulant and convulsant effects at equimolar concentrations. Overall penetrability into cerebrospinal fluid of 4-AP is significantly higher than that of 3,4-DAP after single i.v. administration as evaluated by a high-performance liquid chromatographic determination. The present results can account for the lower central nervous system toxicity of 3,4-DAP when compared to 4-AP previously described after systemic administration.

Evidence for (+)-cicletanine sulfate as an active natriuretic metabolite of cicletanine in the rat.

It was previously shown that the urinary sulfo-conjugate metabolite of cicletanine (cicletanine sulfate), and not free cicletanine, is salidiuretic in rats. Here we investigated potential differences between the resolved (+/-) enantiomers of cicletanine sulfate. Two groups of rats (n = 10) received either (+)- or (-)-cicletanine p.o. High performance capillary electrophoresis revealed that the 24-h urinary excretion of (+)-cicletanine sulfate was 5 times higher than that of (-)-cicletanine sulfate (18.9% vs. 3.8% of the oral dose). The same relative trend was observed after 5 and 10 days of oral administration. Following direct administration into the renal artery of anesthetized rats, (+)-cicletanine sulfate was 3-4 times more potent, in terms of active doses, than (-)-cicletanine sulfate to increase sodium excretion (ED50 = 1.86 +/- 0.28 mg/kg vs. 6.1 +/- 1.0 mg/kg, mean +/- S.E.M., n = 4). The maximal natriuretic potency of (+)-cicletanine sulfate was intermediate between that of furosemide and DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonate). In rat erythrocytes, (+)-cicletanine sulfate was between 2 and 3 times more potent to inhibit the Na(+)-dependent Cl-/HCO3- anion exchanger than (-)-cicletanine sulfate (IC50 = 61 +/- 3 microM vs. 142 +/- 31 microM, n = 4). In conclusion, (+)-cicletanine was more sulfo-conjugated and more potent natriuretic agent in rats than (-)-cicletanine. These results strongly suggest that (+)-cicletanine sulfate is the active natriuretic metabolite of racemic cicletanine in rats. This compound may probably act by inhibiting the Na(+)-dependent Cl-/HCO3- anion exchanger at the cortical diluting segment.

Induction and inhibition of cicletanine metabolism in cultured hepatocytes and liver microsomes from rats.

Cicletanine, a racemic furopyridine derivative synthesized as racemate, is used as an antihypertensive agent. Its two enantiomers are involved in the pharmacological effects of the drug. Cicletanine is metabolized by conjugation enzyme systems (phase II) into sulfoconjugated or glucuroconjugated enantiomers. This study reports on the use of both the induction with 3-methylcholanthrene (3-MC) or phenobarbital (PB) and inhibition with selective compounds to determine and identify UGT isoenzymes involved in the metabolism of cicletanine enantiomers. PB and 3-MC both enhanced the cicletanine enantiomer glucuronidation. These two compounds being known as inducing agents of UGT2B1 and UGTIA6 isoforms, respectively, this suggests an implication of UGT2B1 and UGT1A6 isoforms in the metabolism of the two cicletanine enantiomers: ( + )-cicletanine and ( - )-cicletanine. The use of selective compounds for inhibition study evidenced, in addition to UGT2B1 and UGT1A6 isoforms, the involvement of other UGT isoforms such as UGT1A1, UGT2B7 and UGT2B15 in cicletanine metabolism.

Gallium chloride effects on neonatal rat heart cells in culture, in standard and oxidative conditions.

The effects of gallium chloride (GaCl3) at 7.17, 28.68 and 114.7 microns (0.5, 2 and 8 mg/l of Ga3+) were checked in cardiac cells derived from 2-4 day-old newborn rats, cultured for 72 h in Eagle's minimum essential medium (MEM), enriched with 10% foetal calf serum (v/v) and 2 mM of glutamine at 37 degrees C, with 95% air plus 5% CO2. After 3 hours of standard culture conditions (MEM with glucose 5 mM), Ga treatment induced an increase of glycogen stores without any influence on ATP, ADP, and AMP concentrations. A slight and transient decrease in the beat rate was noted after 15 min of exposure to GaCl3 at all concentrations, whereas there was no difference in the beat rate nor in the cell contraction amplitude after 3 hours of exposure. After 1.5 h in conditions of oxidation (Tyrode solution without glucose, FeCl2 20 microM, ascorbic acid 0.2 mM), GaCl3 at 8 mg/l decreased the malondialdehyde (MDA) production as assessed by the decrease of intracellular concentrations and the decrease of its release in the supernatant. The decreased MDA production following oxidative stress, the increase in glycogen stores in normal oxygen concentrations, as well as the maintenance of ATP concentrations and the lack of any chronotropic effect induced by GaCl3 suggests a protective rather than a deleterious cardiac effect.

Comparative pharmacokinetics of two diastereoisomers dexamethasone and betamethasone in plasma and cerebrospinal fluid in rabbits.

The two diastereoisomers dexamethasone (DXM) and betamethasone (BTM) were infused at two different doses (2, 10 mg.kg-1) in anesthetized rabbits. Samples of plasma and cerebrospinal fluid were collected over a 180-min period. Steroid concentrations were measured by high performance liquid chromatography. The terminal half life (85.7 +/- 20.8 min and 102.2 +/- 29.6 min for DXM; 117.6 +/- 19.8 min and 118.5 +/- 15.8 min for BTM) and the mean residence time (121.4 +/- 27.7 min and 146.1 +/- 41.3 min for DXM; 168.6 +/- 28.1 min and 172.2 +/- 20.6 min for BTM) were unchanged between the doses. Dose-dependent changes in the area under the curve normalized by the dose, then volume distribution and clearance were observed. The average percentage of DXM and BTM bound to plasma proteins were 78.1 +/- 11.5% and 88.3 +/- 5.1% respectively at the lower dose, and decreased significantly with 10 mg.kg-1. DXM appeared more rapidly in the CSF, the highest concentrations of DXM were obtained within 15 min after the end of the injection. The CSF levels were lower than that of plasma unbound and the passage through the blood-brain barrier was saturable. These results will complicate pharmacokinetic and pharmacodynamic analysis.

Influence of sex and oestrogen replacement on the disposition of dexamethasone in rats.

The disposition of dexamethasone (DXM, 2 mg/kg, iv) was studied in ovariectomized female rats treated with oestrogen (0.1 mg and 1 mg of oestradiol benzoate) and in male rats. Oestradiol replacement had no effect on body or liver weights or on the DXM pharmacokinetic parameters (CL, Vdss, AUC, MRT and t1/2) of the female groups. If the Vdss seemed slightly greater in male than in female rats, this difference disappeared after normalization based on body weight. In contrast, CL was greater in the male rats even after normalization. For all the animals, significant correlations were observed between body weight and Vdss (r = 0.731, P less than 0.001) or CL (r = 0.639, P less than 0.001). Terminal half life and MRT were negatively correlated with CL (r = -0.481, P less than 0.01 and r = -0.575, P less than 0.01, respectively) but not with Vdss. Although oestrogen replacement did not seem to affect the pharmacokinetics of DXM, the increase in the CL in male rats should be the main determinant observed between the sexes. These results are consistent with a slower metabolism found for various drugs metabolized by the cytochrome P-450 in female rats.

Metabolism and toxicity of coumarin on cultured human, rat, mouse and rabbit hepatocytes.

We compared the cytotoxic effect of coumarin and its derivatives, 7-hydroxycoumarin (7-OHC), 4-hydroxycoumarin (4-OHC), o-hydroxyphenyl acetic acid (OHPAA) and o-coumaric acid (CA), on cultured hepatocytes from human, rat, mouse and rabbit liver. At 10(-5) and 5 x 10(-5) M, coumarin and its derivatives did not give rise to any signs of toxicity on cultured hepatocytes of the four species. At 10(-4) M, coumarin, but not its derivatives, induced release of lactate dehydrogenase (LDH) into the medium, especially in rat hepatocyte cultures. Intracellular LDH activities were correspondingly reduced. The cytotoxic effect of coumarin in cultured rat hepatocytes was evidenced on morphological examination and from the results of the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium (MTT) reduction test. At higher concentrations (5 x 10(-4) M), 7-OHC and CA were also found to be cytotoxic in cultured rat hepatocytes. The cytotoxic effect of coumarin (5 x 10(-4) M) was decreased in the presence of SKF 525-A, a cytochrome P450 inhibitor. Interspecies comparisons showed that rat hepatocytes were the most sensitive to the toxicity of coumarin and its derivatives, whereas human hepatocytes were the most resistant. Our results suggest that the cytotoxicity of coumarin is metabolism and species-dependent. Thus, the rat may not be a suitable model for evaluating the pharmacological hazards of coumarin in humans.

Effects of oxazepam and acetaminophen on cicletanine metabolism in rat hepatocytes and liver microsomes.

Cicletanine, a racemic furopyridine derivative synthesized as racemate, is used as an antihypertensive agent. Its two enantiomers are involved in the pharmacological effects of the drug. Cicletanine is metabolized by conjugation enzyme systems (phase II) into sulfoconjugated or glucuroconjugated enantiomers. As oxazepam and acetaminophen are widely prescribed, especially to elderly patients, these two drugs may be co-administered with cicletanine. The metabolic profile and the kinetics of biotransformation were studied by using rat hepatocytes and liver microsomes. Cicletanine was extensively metabolized by rat hepatocytes. More than 80% of the drug was biotransformed after a 3 h incubation. The formation of glucuroconjugated metabolites was characterized by the following kinetic parameters, i.e. Vmax = 2.05 +/- 0.21 nmol/min/mg protein and Km = 287 +/- 6.7 microM for (-)-cicletanine, and Vmax = 1.44 +/- 0.12 nmol/min/mg protein and K(m) = 171 +/- 4.1 microM for (+)-cicletanine. Oxazepam inhibited the glucuronidation of cicletanine in both rat hepatocytes and liver microsomes with a competitive-type inhibition, i.e. K(i) = 129 +/- 7.5 and 152 +/- 19.7 microM for (-)-cicletanine and (+)-cicletanine, respectively. The co-incubation of acetaminophen with cicletanine showed that only sulfoconjugation was inhibited in rat hepatocytes. Glucuronidation was not modified by acetaminophen. As natriuric activity is due to sulfoconjugated (+)-cicletanine, acetaminophen could potentially modulate in vivo the pharmacological effect of cicletanine. The data of the in vitro study reported here suggested an interaction between cicletanine and oxazepam or cicletanine and acetaminophen. However, the clinical impact of such a drug interaction needs further evaluation.

Acute effects of gallium chloride on ventricular function and metabolism of the Langendorff perfused rat heart.

The effects of two concentrations of GaCl3 (1.79 microM and 7.17 microM) were studied on isolated perfused paced rat hearts. All hearts were submitted to an equilibration period of 20 minutes under normal conditions of oxygenation (95% O2, 5% CO2) and with 11 mM glucose in Krebs-Henseleit buffer. At the end of the perfusion (80 min) tissue Ga contents were 98.0 +/- 13.8 and 200.2 +/- 28.5 nM/g of wet weight for the lower and the higher Ga concentrations respectively. Left ventricular developed pressure (LVdp) as well as +LVdp/dt and -LVdp/dt were similar in control and Ga-treated groups during the 60 minutes following the equilibration period. At the same time mean coronary flow and oxygen consumption were lower (p < 0.05) in hearts perfused with 7.17 microM Ga than in the control group. Lactate production did not differ in the control and Ga-treated groups. Mean creatine kinase release was lower (p < 0.05) in the 7.17 microM Ga-treated group than in the 1.79 microM Ga-treated and control groups. Intratissular malondialdehyde as well as glycogen and ATP concentrations did not differ in all groups at the end of the experiment. Gallium chloride partially prevented the unavoidable oedema resulting from using saline Krebs-Henseleit solution. In conclusion, acute GaCl3 administration improves the functionality of the Langendorff-heart model.

Increased iron content in rat myocardium after 5-fluorouracil chronic administration.

The isovolumic perfused rat heart model according to Langendorff has been used in order to characterize the changes occurring in the heart following 5-Fluorouracil (5-FU) administration. Preliminary published data pointed out that perfusion of isolated heart with 1 mg/l 5-FU failed to show any differences in contractility and oxygen consumption in comparison with the control group. However, when Wistar rats received 5-FU once a day (50 mg/kg, I.P.) for five consecutive days a consistent increase in oxygen consumption throughout the 80 min of perfusion associated with a decrease in the fractional extraction of oxygen and a lowered + dP/dt max were observed, without any drug added during the in vitro perfusion. Further investigation has been performed for a better understanding of the results observed after 5-FU pretreatment. Magnesium, potassium, calcium, copper and iron contents in the myocardium (at 0 min of perfusion) were measured by flame atomic absorption spectrophotometry. Iron levels were 20% higher in the 5-FU pretreated group than in the control group, whereas as no differences were observed for the other elemental concentrations. Both initial glycogen and ATP contents were respectively 42% and 29% higher in the pretreated than in the control group and alpha-hydroxybutyrate dehydrogenase release was lower after 40 min of perfusion in the pretreated group. However, 5-FU pretreatment increased net tissue water gain after 80 min of perfusion. Increases in mean oxygen partial pressure in the myocardium and in oxygen consumption associated with increased iron level might be candidates responsible for 5-FU induced cardiotoxicity through an increased in oxygen derived free radicals. Sympathetic over-stimulation or calcium overload do not appear to be involved in 5-FU induced cardiotoxicity.

The effects of 5-fluorouracil on contractility and oxygen uptake of the isolated perfused rat heart.

Clinical cardiotoxicity related to 5-fluorouracil (5-FU) simulates either myocardial ischemia or left ventricular dysfunction. In order to characterize the changes occurring in the heart following 5-FU administration, the isovolumic perfused rat heart model according to Langendorff has been used. Particular emphasis was laid on contractility and oxygen uptake. Perfusion of isolated hearts with 1 mg/L 5-FU for 80 minutes failed to show any differences in contractility and oxygen consumption in comparison with the control group. On the contrary, 5-FU pretreatment of Wistar rats (50 mg/kg I.P. for 5 consecutive days) led to a decrease in inotropism without any change in maximum relaxation rate. The most significant finding was the consistent increase in oxygen consumption throughout the 80 minutes of perfusion (p less than 0.05) associated with a decrease in the fractional extraction of oxygen. Mean coronary flow was consistently increased in the 5-FU-pretreated group. Lactate release and CK Leakage did not differ in the two groups. In the 5-FU-pretreated group the ratio of oxygen consumption to rate-pressure product remained significantly elevated throughout 80 minutes of perfusion in comparison with the control group (p less than 0.05). Inappropriately high oxygen uptake could be a reflection of cellular metabolic disturbances responsible for post-ischemic dysfunction.

Clinical pharmacology of gallium chloride after oral administration in lung cancer patients.

Pharmacokinetic parameters were determined in 18 lung cancer patients after a single administration of 800 mg/24 h of GaCl3: Cmax = 123 +/- 61 mu/l; Tmax = 5.2 +/- 5.5 h; AUCO-96h = 4690 +/- 3358 micrograms.l-1.h; AUCO - infinity = 6394 +/- 5352 micrograms.l-1.h; T 1/2 beta = 43 +/- 19 h. Serum Ga concentrations at the steady-state (Css) were then determined in these patients after a daily oral administration of 800 mg/24 h of GaCl3 for 15 days: Css = 274 +/- 167 micrograms/l. No correlation was found between Css and the previous pharmacokinetic parameters in each patient. Various doses of GaCl3 were administered daily to 45 patients to correlate Css and dosage. Serum Ga concentrations increased with dosage from 100 to 400 mg/24 h (p less than 0.05), but not with further dosages up to 1400 mg/24 h. The optimal daily dose of GaCl3 in lung cancer patients seems to be 400 mg/24 h. In 2 patients, Ga was assayed after death in tissues. Ga concentrations were more than 10 micrograms/g in metastases, 3.6 +/- 2.9 micrograms/g in the primary tumor and 2.3 +/- 0.9 micrograms/g in the kidney. Due to the lack of renal and hematological toxicities and the significant uptake of Ga by the tumor, GaCl3 can be used orally in conjunction with other cytotoxic agents. We intend to evaluate its efficacy according to a randomized study comparing chemotherapy versus chemotherapy plus 400 mg/24 h of GaCl3.

Distribution of gacyclidine enantiomers after experimental spinal cord injury in rats: possible involvement of an active transport system.

The pharmacokinetics of gacyclidine enantiomers, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, were studied in plasma and spinal cord extracellular fluid (ECF) after experimental spinal cord injury in rats. Spinal cord trauma was produced by introducing an inflatable balloon in the dorsal subdural space. Upon implantation of microdialysis probes in spinal cord (T9) and intravenous (iv) bolus administration of (+/-)-gacyclidine (2.5 mg/kg), concentrations in plasma and ECF were monitored over 5 h and analyzed by a stereospecific gas chromatography-mass spectrometry (GC-MS) assay. In plasma, concentrations of (+)-gacyclidine were approximately 25% higher than those of (-)-gacyclidine over the duration of the experiment and decayed in parallel (t(1/2 alpha) approximately 7 min; t(1/2 beta) approximately 90 min) with no significant difference between the two enantiomers. Clearance (CL) and volume of distribution (Vd) of (-)-gacyclidine were approximately 20% higher than those of its optical antipode (CL: 285 versus 236 mL. kg(-1). min(-1); Vd(beta): 39.3 versus 31.2 l/kg). Protein binding (approximately 91%) was not stereoselective. In spinal cord ECF, both enantiomers were quantifiable within 10 min after drug administration, and their concentration remained stable over the duration of the experiment in spite of changing blood concentrations. Repeated iv bolus injections of gacyclidine did not modify these profiles. Areas under the curves (AUCs) of concentration in ECF versus time were similar for both enantiomers and not correlated with AUCs in plasma. Penetration of (-)-gacyclidine was, however, significantly higher (approximately 30%) than that of (+)-gacyclidine. In summary, the disposition of gacyclidine enantiomers is stereoselective. Both enantiomers exhibit a high affinity for spinal cord tissue, and the drug exchange between plasma and spinal cord ECF involves an active transport system. These findings contribute to the explanation of the discrepancy between drug concentrations in plasma and spinal cord ECF.

Pharmacokinetics of gacyclidine enantiomers in plasma and spinal cord after single enantiomer administration in rats.

The purpose of this study was to determine the pharmacokinetics of gacyclidine, a non-competitive NMDA antagonist, in plasma and spinal cord extracellular fluid (ECF) after IV administration of single enantiomers in rats. After implantation of microdialysis probes in spinal cord, concentrations in plasma and ECF dialysates were determined by a chiral GC/MS assay over 5 h after administration of either (+)-gacyclidine or (-)-gacyclidine (1.25 mg/kg). Plasma protein binding was estimated in vitro by equilibrium dialysis. Plasma concentrations decayed in parallel in a biphasic manner (t(1/2)alpha approximately 9 min; t(1/2)beta approximately 90 min) with no significant difference between the two enantiomers. Clearance of (+)-gacyclidine and (-)-gacyclidine (291 versus 275 ml/min per kg, respectively), volume of distribution (Vdbeta: 38 versus 40 l/kg), and protein binding (90 versus 89%) were not stereoselective. Both gacyclidine enantiomers were quantifiable in spinal cord ECF 10 min after drug administration and their concentrations remained stable over the duration of the experiment in spite of changing blood concentrations. Penetration of the two enantiomers in spinal cord ECF was similar although highly variable between animals. Exposure of spinal cord ECF was comparable for both enantiomers, and not correlated with plasma AUCs. This study showed the absence of any pharmacokinetic difference between the two enantiomers when administered individually, and no enantiomeric inversion. Both gacyclidine enantiomers penetrate rapidly and extensively into spinal cord ECF, and their distribution may involve an active transport system.

Pharmacokinetics and brain distribution of zolpidem in the rat after acute and chronic administration.

The pharmacokinetics of zolpidem were studied after single dose, administered for either 7 or 28 days to rats. Thirty minutes after the last dose, animals were killed and the brain removed. The highest concentrations in plasma, which were observed at the first sampling time (0.5 h) were 2341 +/- 540 (day 0), 1956 +/- 325 (day 7) and 2908 +/- 1369 ng mL-1 (day 28). Corresponding AUC values of 1742 +/- 488, 1583 +/- 422 and 2683 +/- 1249 ng mL-1 h were found. MRT increased significantly from 0.46 +/- 0.06 h on day 0 to 0.67 +/- 0.02 h on day 28. The cerebral levels showed no significant change during the chronic administration (766 +/- 285, 685 +/- 171 and 887 +/- 264 ng g-1, respectively). No modification of the principal kinetic parameters was detected up to the 28th day of treatment.

Toloxatone pharmacokinetics in the plasma and cerebrospinal fluid of the rabbit.

The pharmacokinetics of toloxatone (5 and 10 mg kg-1, i.v.) was studied in anaesthetized rabbits. There was a biexponential decline in plasma concentration with time. No differences were observed in the pharmacokinetic parameters with the increase of the dose. The terminal half-life was short (47.4 +/- 2.8 and 41.5 +/- 4.2 min for 5 and 10 mg kg-1, respectively). The total clearance was 79 +/- 18 mL min-1 after a dose of 5 mg kg-1 and 106 +/- 40 mL min-1 after a dose of 10 mg kg-1. The volume of distribution was 5.8 +/- 2.8 (5 mg kg-1) and 5.4 +/- 1.8 L (10 mg kg-1). The average percentage of toloxatone bound to plasma protein was 30% and was not affected by concentrations within the investigated range. In cerebrospinal fluid (CSF), the highest concentrations of toloxatone were obtained within 15 min after the end of the injection. The CSF level of toloxatone was equal to that of plasma unbound toloxatone and declined at a rate similar to toloxatone in plasma. These results suggest that the toloxatone passage through the blood-brain barrier may be completed by passive diffusion. In addition, the unbound plasma concentration would accurately reflect the toloxatone concentration in CSF and could be a useful tool for drug monitoring.

Arterio-venous ethanol levels in blood and plasma after intravenous injection in rabbits.

Arterio-venous ethanol concentrations in both whole blood and plasma were determined as a function of time in the rabbit. Following i.v. injection of 1.0 g/kg, both arterial and venous ethanol concentrations showed an abrupt decline occurring immediately after the end of the administration, followed by a pseudolinear phase that persisted for the length of the experiment. This work substantiates the arterio-venous ethanol concentration differences reported in the literature. It illustrates that equal arterial and venous ethanol concentrations may not be achieved readily after rapid i.v. injection. Moreover, it demonstrates a faster decay of ethanol concentrations in arterial than in venous plasma.

[Pharmacokinetics of dexamethasone administered orally in obese patients]. / Pharmacocinétique de la dexaméthasone par voie orale chez le sujet obèse.

Dexamethasone pharmacokinetics was studied after oral administration of two Décadron tablets in six healthy controls and in eight obese patients whose weight was at least 20% above that of the ideal body weight. The absorption (0.30 +/- 0.09 h and 0.29 +/- 0.08 h) and elimination (4.52 +/- 0.57 h and 3.71 +/- 1.05 h) half-lives were not significantly different. Maximum plasma concentrations were similar (11.95 +/- 1.00 micrograms/l and 10.93 +/- 0.94 micrograms/l) but the lag-time was significantly higher in the obese patients (0.49 +/- 0.12 h and 0.13 +/- 0.04 h). A positive correlation was observed between the AUC and the total body weight (r = 0.738, p less than 0.01). Mean predexamethasone cortisol level was significantly lower in the obese patients (189.20 +/- 52.7 micrograms/l and 256.90 +/- 58 micrograms/l). The pharmacokinetics modifications were not sufficient to explain the increased false positive frequency in the dexamethasone suppression test of the hypothalamic-pituitary-adrenal axis in obesity.

[Chronopharmacokinetics of dexamethasone in young subjects]. / Chronopharmacocinétique de la dexaméthasone chez le sujet jeune.

Dexamethasone chronopharmacokinetics was studied in six young subjects 20 to 30 years old. The randomized cross-over study consisted of evening (11.00 p.m.) or morning (08.00 a.m.) dose separated by a period of one week. After the evening administration of the drug, only Tmax (1.77 +/- 0.74 à 11.00 p.m. and 0.99 +/- 0.64 à 08.00 a.m.) and Cmax/Tmax were higher than those determined at 08.00 a.m. This difference might be related to a cyclic variation of the absorption phase of dexamethasone. Thus, in our study, the time of administration has only a weak effect on the pharmacokinetics of dexamethasone.