Population Pharmacokinetics of Amitriptyline After Intrathecal, Epidural, and Intravenous Administration in Sheep.

BACKGROUND: Amitriptyline (AMI) is a lipophilic, tricyclic antidepressant with analgesic properties that could potentially be used for epidural (EPI) analgesia. However, no pharmacokinetic data are available for AMI in spinal spaces. The objective of this study was to evaluate the spinal disposition and intrathecal (IT) bioavailability of AMI after IT and EPI administration. METHODS: Six Lacaune ewes received 3 consecutive administrations of AMI. They initially received 10 mg of AMI administered intravenously, then 5 mg of AMI administered intrathecally, and 50 mg of AMI injected into the EPI space. Consecutive administrations were separated by intervals of 2 hours. A simultaneous microdialysis technique was used to determine the EPI and IT concentrations of AMI. Population analysis with S-ADAPT software was used to evaluate the pharmacokinetic parameters. RESULTS: Following intravenous administration, the clearance and central compartment (Vc) in plasma were 1.32 L/min and 147 L, respectively. Concentration-time profiles for the IT and EPI compartments were highly variable after transmeningeal diffusion. The IT Vc after IT administration and the EPI Vc after EPI administration were 2.4 and 48.9 mL, respectively. Less AMI transferred from the EPI to the IT space than from the IT to the EPI compartment, with bioavailabilities of 1.3% and 55%, respectively. CONCLUSIONS: Simultaneous population analysis for AMI demonstrated differences in EPI and IT pharmacokinetics following the EPI and IT administration of this drug. The IT bioavailability of AMI after EPI administration is relatively low.

A micro-QuEChERS method coupled to GC-MS for the quantification of pesticides in specific maternal and fetal tissues.

The aim of this study was to establish a new QuEChERS (quick, easy, cheap, effective, rugged and safe) method coupled to gas chromatography-mass spectrometry (GC-MS) detection for the evaluation of the pesticide biodistribution in specific maternal and fetal tissues. This method was validated for the quantification of pesticides such as chlorotriazines (atrazine, simazine and propazine), their chlorinated metabolites (DIA, DEA and DACT). This new QuEChERS method was developed to facilitate extraction from small tissues such as fetal tissues (mean value: 200mg). The limits of detection, quantification, recovery, precision and accuracy were evaluated for different tissues (liver and brain) and blood. LOD and LOQ ranged between 0.34 and 3.27 ng/g and 1.04 to 9.91 ng/g, respectively. Recovery exceeded 80% for all pesticides, except DACT, with an associated RSD<15%. Precision and accuracy satisfied the criteria usually applied in the validation of bioanalytical methods. The results obtained indicate that this technique is suitable for use in studies of the biodistribution of pesticides in fetal tissues and can be used to evaluate the risk of exposure to pesticides during gestation.

In vitro evaluation of diffusion of lidocaine and alkalinized lidocaine through the polyurethane membrane of the endotracheal tube.

OBJECTIVES: Endotracheal tube (ETT) and its inflated cuff are likely to induce specific reactivity at the emergence time. In ICU, the tolerance of the ETT cuff could be a part of patient agitation and increased of sedation. MATERIALS AND METHODS: Using specific ICU ETT cuff (thin polyurethane cuff), we perform an in vitro evaluation of diffusion of lidocaine and alkalinized lidocaine (L-B) across the PU cuff for a long duration. We evaluate the safety of this procedure by a daily injection into the cuff. RESULTS: With lidocaine alone, we observed a low rate of diffusion through the cuff (<8% over 24h), whereas the L-B solution had a high diffusion (>90% over 24h). The released profiles were similar from day 0 to day 8, and no cuff rupture was reported over the 8-day study. CONCLUSION: The safety, controlled release, and lack of deleterious effects on cuff membrane were confirmed. In case of unexpected cuff rupture, an adequate determination of the mixture allows to obtain a safe solution with the achievement of a physiological pH (7.4) and the small dose of lidocaine (40 mg).

Influence of efflux transporters on liver, bile and brain disposition of amitriptyline in mice.

The aim of this work was to clarify the role of Abcb1 and the possible involvement of Abcc2 and Abcg2 in liver, bile and brain disposition of amitriptyline (AMI). AMI was administrated to Abcb1a deficient mice (n=36): CF1 (-/-) and CF1 (+/+) mice received via intraperitoneal route (i.p.) 5 mg/kg AMI and CF1 (+/+) mice received i.p. 5 mg/kg AMI+100 mg/kg quinidine (Abcb1 inhibitor). Then, Swiss mice (n=24) received i.p. 5 mg/kg AMI alone and in association with 200 mg/kg novobiocin (Abcg2 inhibitor), 20 mg/kg probenecid (Abcc2 inhibitor) and 100 mg/kg quinidine. Plasma concentrations of AMI were not influenced by novobiocin, probenecid and the lack of Abcb1, but were significantly increased by quinidine, resulting from the inhibition of hydroxylation mediated by CYP2D6. Brain distribution of AMI was not influenced by the lack of Abcb1 but was slightly significant with quinidine and not with novobiocin and probenecid. At the hepato-biliary interface, we showed the involvement of Abcb1, Abcc2 and Abcg2; indeed, AMI concentration was increased in liver and decreased in bile, where quinidine is the strongest inhibitor, followed by probenecid and novobiocin. These results show that in brain the effect of Abcb1, Abcc2 and Abcg2 should be negligible and that at the hepato-biliary level, Abcb1 plays a predominant role compared to Abcc2 and Abcg2.

Local anaesthetic use for the iliac crest-donor site: pharmacokinetic and pharmacodynamic evaluations.

During orthopaedic surgery of the limb, we performed a prospective, double blind controlled study on three parallel groups in 30 patients to evaluate the pharmacokinetic and pharmacodynamic effect of infiltration of the iliac crest bone graft harvest site with 20 ml of bupivacaine (100 mg), ropivacaine (150 mg) or saline as control group (n = 10 in each group). Then, in a sheep model of iliac crest infiltration, we compared the pharmacokinetics of single administration of plain bupivacaine (100 mg) and bupivacaine (500 mg)-loaded microspheres. In the clinical control group, pain from the iliac crest was worse than pain from the primary surgical site. Pain from the iliac crest was significantly reduced during the first 12 postoperative hours in local anaesthetic groups compared to the control group. However, during this period, pain from the primary surgical site was increased compared to the control group. Finally, there was no difference between the three groups in the average intake of PCA morphine. There was no significant pharmacokinetic and pharmacodynamic difference between plain bupivacaine and ropivacaine. The maximal plasma concentration (Cmax) of ropivacaine and bupivacaine were 964 (282) ng ml(-1) and 638 (366) ng ml(-1), respectively. In the sheep model, it was clearly shown that the release of bupivacaine from microspheres was controlled and prolonged despite the largest dose of bupivacaine used (500 mg; n = 4). Wound infiltration of iliac crest harvest site with local anaesthetic is an easy technique for postoperative analgesia. However, this effect lasts only 12 hours without reducing the morphine consumption due to an increase of pain from the primary surgical site. The local anaesthetic infiltration produced a significant peak of plasma level, which could be dangerous if another infiltration or regional anaesthetic technique was associated with it. Experimentally, as a drug delivery system, the use of local anaesthetic-loaded microspheres could be an interesting alternative.

Mucosal or systemic administration of rE2 glycoprotein antigen loaded PLGA microspheres.

We have evaluated the ability of recombinant E2 antigen, as a surfactant free formulation of poly (D,L-lactide-co-glycolide) (PLGA) microspheres, to elicit a systemic immune response after administration by mucosal routes (oral and nasal) in comparison to intramuscular route. The sequence encoding a truncated E2 glycoprotein of the classical swine fever virus (CSFV) was expressed in insect cells following infection with recombinant baculovirus, as a His-tagged recombinant antigen. The recombinant E2 glycoprotein (rE2) antigen was co-encapsulated with rabbit serum albumin (RSA) as a protein stabilizer. rE2/RSA loaded PLGA microspheres, with a mean diameter of 4 microm were obtained by a water in oil in water solvent extraction method (w/o/w). Rabbits were immunized with 10 microg of rE2 formulated in PLGA microspheres administrated by three different routes (oral, nasal and intramuscular). After 60 days, each rabbit in all three groups was challenge with 5 microg of rE2 glycoprotein solution by intradermal administration. Blood samples were collected weekly for 90 days and specific rE2 antigen antibodies measured. This work showed that rE2 antigen loaded microspheres was able to initiate an immune response. The intradermal challenge after nasal and oral administration had a clear boost effect on the systemic immune response. Moreover, the response after nasal administration was more intense and less variable than oral route. In conclusion, these data demonstrate a high potential of rE2 loaded PLGA microspheres for their use as a mucosal subunit vaccine.

Effect of epinephrine on epidural, intrathecal, and plasma pharmacokinetics of ropivacaine and bupivacaine in sheep.

BACKGROUND: Local vasoconstriction induced by epinephrine added to epidural local anaesthetics has been shown to improve their quality and duration of action in several clinical reports. There are several assumptions on the mechanisms. This study was designed to evaluate the influence of epinephrine on transmeningeal uptake of epidurally administered ropivacaine and bupivacaine by measuring local anaesthetic concentrations in the epidural and intrathecal spaces and in plasma. METHODS: Ropivacaine (50 mg) and bupivacaine (30 mg) were administered epidurally in sheep with and without epinephrine (75 microg). A microdialysis technique was used to simultaneously measure epidural and intrathecal drug concentrations. Resulting dialysate and plasma concentrations were used to calculate pharmacokinetic parameters for ropivacaine and bupivacaine. RESULTS: Co-administration of epinephrine decreased epidural clearance for ropivacaine [0.6 (sd 0.1) vs 0.4 (0.1) ml min(-1)] but not significantly for bupivacaine [1.2 (0.4) vs 0.8 (0.3) ml min(-1)]. The resultant increase in epidural area under the concentration-time curves (31% for ropivacaine and 52% for bupivacaine) was also observed in the intrathecal space (21% increase for ropivacaine and 37% for bupivacaine). There was no significant influence of epinephrine on ropivacaine plasma pharmacokinetics. Plasma Cmax for bupivacaine was decreased. CONCLUSIONS: These results show that epinephrine decreases the clearance and distribution processes involved in epidural disposition of ropivacaine and bupivacaine, leading to an increased uptake into the intrathecal space with an apparent more pronounced effect for bupivacaine.

Bupivacaine containing dry emulsion can prolong epidural anesthetic effects in rabbits.

To assess the prolongation of epidural bupivacaine by a novel lipid formulation, a physically stabilized bupivacaine containing dry emulsion was prepared by spray-drying. Bupivacaine release from the oil-in-water emulsion was studied using an in vitro two-phase stirred model, then the pharmacodynamic effects and the pharmacokinetics of bupivacaine from the spray-dried emulsion were evaluated and compared to a bupivacaine hydrochloride solution, following a two-period cross-over epidural administration in rabbits. The in vitro release characteristics suggested an extended release of bupivacaine from the emulsion compared to the solution. From the in vivo study, C(max) obtained with the emulsion (containing 5 mg bupivacaine) was not statistically different than from the solution (containing 2 mg bupivacaine) while T(max) was increased, suggesting a diminution of bupivacaine systemic absorption. The onset time of epidural anesthesia was similar for both formulations of bupivacaine used, while a significant blockade prolongation (360%) was observed with the emulsion compared to the solution, suggesting a controlled release of bupivacaine. Dry emulsions could be promising dosage forms to optimize the disposition of epidurally administered LAs.

Alkalinization of intra-cuff lidocaine and use of gel lubrication protect against tracheal tube-induced emergence phenomena.

BACKGROUND: We sought to determine the benefits of using alkalinized lidocaine 40 mg to fill the cuff of a tracheal tube (ETT) in combination with water-soluble gel lubrication to prevent post-intubation sore throat. METHODS: The work included an in vitro study of the diffusion of alkalinized lidocaine solution through the low-pressure, high-volume cuff of an ETT. We also performed a randomized controlled study (n=20 patients in each group) that included a group who received an alkalinized lidocaine-filled ETT cuff with lubrication of the tube using water-soluble gel (Group G), and two control groups who received an alkalinized lidocaine-filled cuff with ETT lubrication with water (Group W) or an air-filled cuff with ETT lubrication with water (Group C). RESULTS: Water-soluble gel lubrication (Group G) produced a lower incidence of sore throat during the 24-h post-extubation period than lubrication with water alone in the cuffs filled with alkalinized lidocaine (Group W), and compared with the air control group. The ability of lidocaine to pass through the cuff of an ETT when water-soluble gel and/or water alone was used as a lubricant was similar, as determined by lidocaine plasma concentrations (C(max) 45 ng x ml(-1)). Cough and restlessness before tracheal extubation were decreased in patients with the alkalinized lidocaine-filled cuffs compared with the air-filled cuffs. After extubation, nausea, vomiting, dysphonia and hoarseness were greater for patients with air-filled cuffs compared with the lidocaine-filled cuffs. No significant difference between the groups was recorded in arterial blood pressure and heart rate. In vitro data suggest that the lower the NaHCO(3) injection volume, the greater the release of lidocaine across a low-pressure, high-volume cuff. CONCLUSIONS: These data show benefits of using an alkalinized lidocaine-filled ETT cuff in combination with water-soluble gel lubrication in preventing post-intubation sore throat.

Effect of dexamethasone on motor brachial plexus block with bupivacaine and with bupivacaine-loaded microspheres in a sheep model.

BACKGROUND AND OBJECTIVE: It has been suggested that dexamethasone potentiates the sensory block produced by bupivacaine when both drugs are loaded in microspheres. The aim of the study was to evaluate the effect of dexamethasone on the brachial plexus block obtained with plain bupivacaine and bupivacaine-loaded microspheres. METHODS: Dexamethasone alone (Group 5) or added to plain bupivacaine (75 mg) with (Groups 3 and 4) and without pH correction (Group 2) was compared with plain bupivacaine (75 mg; Group 1). The effect of a small dose of dexamethasone (0.42 mg) was then evaluated on the brachial plexus block obtained with bupivacaine (750 mg) as bupivacaine-loaded microspheres (Group 6). Dexamethasone was added either in the suspending medium (Group 7) or incorporated with bupivacaine into microspheres (Group 8). The motor block was evaluated in a plexus brachial sheep model. RESULTS: Dexamethasone alone did not produce any motor block. When added to plain bupivacaine without pH correction, complete motor block could not be obtained. When the pH was corrected, addition of dexamethasone to plain bupivacaine seemed to delay the onset of motor block and did not prolong its duration, and it had no effect on the pharmacokinetics of bupivacaine. With bupivacaine-loaded microspheres, the duration of complete motor block was reduced when a small dose of dexamethasone was added in the suspending medium. However, the duration of motor block was significantly prolonged when dexamethasone was incorporated with bupivacaine into microspheres. CONCLUSIONS: Despite the delayed onset of motor block, the incorporation of dexamethasone in bupivacaine-loaded microspheres dramatically increases the duration of action (700 +/- 485-5160 +/- 2136 min), which could be clinically relevant when such a drug-delivery system will be available.

The pharmacokinetics and pharmacodynamics of bupivacaine-loaded microspheres on a brachial plexus block model in sheep.

UNLABELLED: We evaluated bupivacaine-loaded microspheres (B-Ms) using a brachial plexus block model in sheep. In the first step, pharmacokinetic characterization of 75 mg bupivacaine hydrochloride (B-HCl) (IV infusion and brachial plexus block) was performed (n = 12). In the second step, a brachial plexus block dose response study of B-HCl was performed with 37.5 mg, 75 mg, 150 mg, 300 mg, and 750 mg. As a comparison, evaluations were performed using a 750-mg bupivacaine base (B). In the third step, evaluations of brachial plexus block were performed with B-Ms (750 mg of B as B-Ms) using two formulations, 60/40 and 50/50 (w/w %); drug-free microspheres were also evaluated. Toxicity evaluations were also performed after IV administration of B-HCl (750 mg and 300 mg), B-Ms (750 mg), and drug-free microspheres (30 mL over 1 min). As the B-HCl dose increased, the time of onset of block decreased and the duration of complete motor blockade increased at the expense of an increase in bupivacaine plasma concentrations. The time of maximum concentration appeared to be independent of the B-HCl dose. In brachial plexus block, a 37.5-mg dose of B-HCl did not induce motor blockade whereas a dose of 750 mg of B-HCl was clinically toxic. In the case of IV administration, doses of 300 mg of B-HCl were as toxic as 750 mg of B-HCl. Compared with the 75 mg of B-HCl administration for brachial plexus block, administration of 750 mg of B as B-Ms increased the duration of complete motor blockade without significant difference in maximum concentration. No significant clinical difference between the two formulations of B-Ms was demonstrated. The IV administration of B-Ms was safe. We conclude that the controlled release of bupivacaine from microspheres prolonged the brachial plexus block without obvious toxicity. IMPLICATIONS: Administration of 750 mg of bupivacaine as loaded-microspheres resulted in prolongation of brachial plexus block in sheep. The peak plasma concentration was not significantly larger than that obtained with 75 mg of plain bupivacaine. The motor blockade was increased more than six times compared with 75 mg plain bupivacaine.

Endotracheal tube cuffs filled with lidocaine as a drug delivery system: in vitro and in vivo investigations.

The purpose of this study was to examine if lidocaine diffusion across an endotracheal tube cuff could improve post-operative tolerance, especially sore throat. The in vitro release of lidocaine from tube cuffs filled with different lidocaine formulations (base form, hydrochloride form or alkalinized lidocaine hydrochloride) was investigated. A preliminary pilot clinical study in anaesthesia for spine surgery in smoker patients was carried out to examine the pharmacokinetic (i.e. systemic uptake) and pharmacodynamic effects (i.e. incidence of sore throat) obtained with the endotracheal tube cuff filled with lidocaine solution, compared to cuffs inflated only with air. From our in vitro experiment, only the hydrophobic neutral base form of lidocaine was able to diffuse (65.1+/-1.1% released after 6 h), while for the charged hydrochloride form, only a permeation phenomenon occurred concerning only 1% of the total drug. Alkalinization of lidocaine hydrochloride (the only form available as a drug) allows smaller amounts to be used compared to previous published studies (20-40 mg vs. 200-500 mg) and no lag time for diffusion. Such a system could provide a controlled release reservoir for lidocaine to adjacent tracheal tissue. This was shown in our pilot study with sustained plasmatic profiles and improved tolerance (decreased pain scores) in the rank order: air group<

Spinal biopharmaceutics of bupivacaine and lidocaine by microdialysis after their simultaneous administration in rabbits.

The aim of the present study was to determine the intrathecal bioavailability of a mixture of lidocaine and bupivacaine in a rabbit model of spinal anesthesia by using the microdialysis technique. Catheter and microdialysis probe were inserted under control of the view either in the epidural or in the intrathecal space. First, the epidural disposition of the mixture of bupivacaine and lidocaine was studied after epidural administration. Then, the intrathecal and plasma dispositions of bupivacaine and lidocaine were investigated following intrathecal or epidural administration. The epidural clearance of bupivacaine was higher than that of lidocaine, suggesting a more significant uptake of bupivacaine into the systemic circulation and/or into the CSF. The intrathecal bioavailability of bupivacaine and lidocaine was 12.3 and 17.9%, respectively, while it was 5.5 and 17.7% following the separate administration of each agent [Clément, R., Malinovsky, J.M., Le Corre, P., Dollo, G., Chevanne, F., Le Verge, R., 1999. Cerebrospinal fluid bioavailability and pharmacokinetics of bupivacaine and lidocaine following intrathecal and epidural administrations in rabbits using microdialysis. J. Pharmacol. Exp. Ther. 289, 1015-21]. After intrathecal administration, a decrease in C(max) and AUC values was observed for bupivacaine in comparison with the separate administration. Moreover, after epidural administration, the systemic resorption was slower and lower, especially for bupivacaine. Such a reduction in the systemic absorption of bupivacaine might increase its intrathecal bioavailability, resulting from a vasoconstrictor effect of lidocaine reducing the systemic absorption of bupivacaine from the epidural space leading to an increase of its extent of absorption through meninges into CSF although its absorption rate was not modified.

[Biopharmaceutics of local anesthetic-cyclodextrin complexes following loco-regional administration]. / Biopharmacie de complexes anesthésiques locaux-cyclodextrines après administration loco-régionale.

In the research of new dosage forms improving the therapeutic index of local anesthetics, we studied cyclodextrins, cyclic oligosaccharides forming soluble inclusion complexes with various lipophilic drugs. Complexes between bupivacaine and hydroxypropyl-B-cyclodextrin, bupivacaine and sulfobutyl ether-7-B-cyclodextrin were studied in vivo, using an epidural and a perineural (sciatic) model, respectively. Biopharmaceutics and pharmacodynamics of bupivacaine were evaluated in the rabbit. In both models, only systemic absorption rate of bupivacaine was decreased upon complexation, not the quantity absorbed. Complexation with cyclodextrins could be a promising drug delivery system to improve the therapeutic index of local anesthetics.

Biopharmaceutics and pharmacokinetics of 5-phenyl-1, 2-dithiole-3-thione complexed with sulfobutyl ether-7-beta-cyclodextrin in rabbits.

The biopharmaceutics and pharmacokinetics of 5-phenyl-1, 2-dithiole-3-thione (5PDTT) were investigated in rabbits, after administration as a complex with sulfobutyl-ether-7-beta-cyclodextrin (SBE7-beta-CD) by intravenous and oral routes and as a micronized powder by oral route. 5PDTT had a rapid and large red blood cell partitioning that was not dependent on drug concentration either in vitro or ex vivo. The blood clearance was very high (354 +/- 131 mL/min) suggesting extrahepatic metabolism and/or nonrenal elimination and a significant volume of distribution (67 +/- 76 L). The renal clearance was 0.17% of total clearance. 5-phenyl-1,2-dithiol-3-one (5PDTO) was identified as a metabolite in blood and urine. The bioavailability of 5PDTT following administration of 5PDTT/SBE7-beta-CD complex was estimated to 41% while it was close to zero when 5PDTT was given as a micronized powder.

Improvement in solubility and dissolution rate of 1, 2-dithiole-3-thiones upon complexation with beta-cyclodextrin and its hydroxypropyl and sulfobutyl ether-7 derivatives.

Inclusion complexes between beta-cyclodextrin derivatives and 1, 2-dithione-3-thiones were studied in aqueous solution and in the solid state. Phase solubility study was used to evaluate the complexation in solution, at 37 degrees C, of three cyclodextrins, i. e., beta-cyclodextrin (betaCD), hydroxypropyl-beta-cyclodextrin (HPbetaCD), sulfobutyl ether-7-beta-cyclodextrin (SBE7betaCD), and four 1,2-dithiole-3-thiones, i.e., the parent compound dithiolethione (DTT), dimethyldithiolethione (DMDTT), 5-phenyldithiolethione (5PDTT), and anetholetrithione (ATT). Stability constants of the DTT complexes with HPbetaCD and SBE7betaCD were also determined spectrophotometrically using a nonlinear least-squares methodology. Differential scanning calorimetry (DSC) and scanning electronic microscopy (SEM) were used to characterize spray-dried complexes formed between 5PDTT and SBE7betaCD, ATT and SBE7betaCD. Dissolution studies using the USP paddle method were carried out in water at 37 degrees C for both ATT and 5PDTT binary systems with HPbetaCD and SBE7betaCD. Solubility enhancements were much greater with the more lipophilic ATT and 5PDTT compared to DTT and DMDTT, whatever the cyclodextrin used, in the rank order SBE7betaCD > HPbetaCD >> betaCD. Stability constants obtained (between 120 and 12800 mol(-1)) were also the highest for the more lipophilic drugs and in the same rank order SBE7betaCD > HPbetaCD >> betaCD. Results obtained by UV spectrophotometry were in good agreement with those obtained by phase-solubility study. DSC thermograms of spray-dried complexes of ATT and 5PDTT with HPbetaCD and SBE7betaCD lacked the endothermal peak of pure drug peak which was found for the physical mixtures (107 degrees C and 125 degrees C for ATT and 5PDTT, respectively). Finally, dissolution profiles of spray-dried inclusion complexes studied displayed a faster dissolution rate compared to physical mixtures and pure drugs. The present study showed that complexation of 1,2-dithiole-3-thiones with beta-cyclodextrin derivatives resulted in an increase in solubility, allowing intravenous formulation for bioavailability and metabolism studies and an increase in the dissolution rate of the drugs, which should be of interest for oral absorption of these lipophilic compounds.

Biopharmaceutics and metabolism of yohimbine in humans.

The biopharmaceutics of yohimbine (YO) and the pharmacokinetics of 10-hydroxy-yohimbine (10-OH-YO) and 11-hydroxy-yohimbine (11-OH-YO) were investigated in healthy subjects following i.v. (5 mg) and oral (8 mg) dosing. One subject was found as a slow hydroxylator of YO. The mean (+/-S.D.) oral absolute bioavailability of YO was 22.3+/-21. 5%. Total plasma clearance (CL) and renal clearance (CL(r)) of YO following i.v. dosing were 0.728+/-0.256 ml/min and 0.001+/-0.002 ml/min, respectively. Based on the steady-state volume of distribution (V(ss)), YO had a relatively low distribution (V(ss) = 32.2+/-12.1 l). The overall renal excretion of YO, 10-OH-YO and 11-OH-YO, expressed as percent of the dose of YO administered, were not different following i.v. and oral dosing, and were around 0.1, 0.2 and 14%, respectively. Following i.v. dosing of YO, the mean apparent terminal half-life of 11-OH-YO (347+/-63 min) was almost four times higher than that of YO (91.0+/-33.6 min) suggesting an elimination rate-limited kinetics for 11-OH-YO.

[Bioavailability of phloroglucinol in man]. / Biodisponibilité du phloroglucinol chez l'homme.

This work reports a bioavailability study between two oral dosage forms containing 125.2 mg active phloroglucinol. Twelve healthy volunteers subjects received a sublingual administration of both dosage forms, a flash liberation tablet and a freeze-dried reference tablet (lyoc), according to a randomized and cross-over design. An accurate, sensitive and specific high performance liquid chromatographic method was developed for the determination of free phloroglucinol as well as its conjugated metabolites, that allowed as to clarify phloroglucinol pharmacokinetic behaviour in man, specially its important metabolisation, its poor systemic bioavailability after oral administration and its total urinary elimination mainly under metabolized form. Total plasmatic phloroglucinol pharmacokinetic profiles led to pertinent parameters needed for statistical bioequivalence study, i.e. T1/2 alpha, T1/2 beta, AUC, Tmax, Cmax and MRT. The mean comparative values of these parameters showed the equivalent performances of both oral dosage forms studied and the statistical tests performed (ANOVA, Westlake and two one-sided t test) concluded to their bioequivalence.