Biomedical subjects
G Houin
Publications and source records attributed to G Houin.
A pharmacokinetic model for multiple sites discontinuous gastrointestinal absorption.
PURPOSE: To build a pharmacokinetic model taking into account a discontinuous absorption along the gut, from n successive sites, a non-absorbing intestinal segment being always in between two successive sites. To solve the mathematical model linked with the pharmacokinetic model to obtain the concentration and contribution of each site to absorption, area under curve and bioavailability. METHODS: Whatever the number n of sites, we obtained the Laplace transform of amounts of drug in each site, then plasma concentration, so that concentration or AUC were expressed analytically. When only two absorption sites are present, concentration is obtained from Heaviside's theorem; but for n> or =3, Bromwich's theorem is necessary, a pole being of the order of more than two. RESULTS: Simulations performed with data gathered from the literature allow to find, with n=2 sites, the particular case used for ranitinine and to show the efficacy of each site. For n=3 sites, real data exhibiting three peaks of various magnitude were fitted on our model. CONCLUSION: This general discontinuous oral absorption pharmacokinetic model may be taken as a possible tool to characterize each site of absorption and to estimate the area under curves or bioavailability.
A pharmacokinetic model for alpha interferon administered subcutaneously.
AIMS: To model the pharmacokinetic profiles of alpha interferon (alphaIFN) after a single subcutaneous (s.c.) injection of 3 million units of alpha 2b interferon, to correlate the pharmacokinetic parameters with patient demographic covariates, and to develop a limiting sampling strategy for determining the alphaIFN plasma area under the curve of concentration vs time (AUC). METHODS: The plasma alphaIFN pharmacokinetics were determined in 27 patients with chronic hepatitis C virus infection after the first s.c. injection of the drug. Ten patients had normal renal function and 17 were chronic haemodialysis patients. Plasma samples were assayed by an Elisa method. Concentration-time data was analysed by a population approach using NONMEM. RESULTS: The pharmacokinetic model which better described the concentration vs time data was a one-compartment model with two processes of absorption: a zero-order followed by a first-order process. The mean clearance of dialysis patients represented 37% (with 95% confidence interval: 30% -44%) of the mean value of the patients with normal renal function. The volume of distribution was significantly correlated to the body surface area. Bayesian analysis using NONMEM allowed determination of the individual plasma AUC from three samples within the 24 h period post s.c. injection. CONCLUSIONS: The present pharmacokinetic model will allow one to obtain individual parameters such as, the area under the curve of concentration vs time from a limited-sampling strategy, and to perform pharmacokinetic-pharmacodynamic analysis of combined alphaIFN plasma concentrations and viraemic data.
Pharmacokinetics, metabolism and excretion of megazol, a new potent trypanocidal drug in animals.
The pharmacokinetics of megazol (CAS 19622-55-0) was investigated after intraperitoneal and oral administration of the drug (80 mg/kg) to mice. The plasma levels were significantly higher after oral administration of drug than after intraperitoneal route (33.8 micrograms/ml compared with 19.0 micrograms/ml for Cmax, 158714 micrograms.h/l compared with 96057 micrograms.h/l for AUC). When suramin (CAS 145-63-1) was administered 24 h before oral administration of megazol, megazol absorption was accelerated (2 h compared with 4 h for Tmax) but the amount absorbed was lower (19.9 micrograms/ml compared with 33.8 micrograms/ml for Cmax and 95547 micrograms.h/l vs 158714 micrograms.h/l for AUC). In the infected mice previously treated with suramin, all estimated pharmacokinetic parameters of plasma megazol were significantly modified, in particularly an increase in the apparent volume of distribution (5.6 l/kg compared with 0.9 l/kg) with a prolongation of the elimination half-life (3 h compared with 0.7 h) of megazol. Excretion of the total radioactivity of megazol was also evaluated after oral administration of 3H-megazol to rats. Total radioactivity was eliminated predominantly via the urinary route (80%) vs. 10.5% in the faeces, 9.5% remaining in the body 8 days after dosing. When unlabelled megazol was orally administered to rats with absence or presence of suramin, megazol recovered in urine and faeces 72 h dosing was: 55.7%/2% vs 20.6%/1.6%, respectively. In the urine, unchanged megazol was present as characterized by LC-MS/MS as well as 4 unknown metabolites. This study indicates that suramin significantly affects the pharmacokinetics of megazol and its elimination.
Pharmacokinetics, metabolism and bioavailability of the new anti-allergic drug BM 113. Part I: Pharmacokinetics and tissular distribution in Sprague-Dawley rats.
A new anti-allergic drug, BM 113 (1-(benzhydryloxyethyl)piperidino-4-ethylacetate, CAS 115313-90-1; BM 113 maleate: CAS 115313-91-2) with a piperidinic structure, showing antihistaminic properties was studied in male and female Sprague-Dawley rats after i.v. or p.o. administrations of 0.750 mg/kg 3H-BM 113. This product presented a rapid faecal elimination after i.v. and oral administration. The total recovery of the dose was obtained after 144 h. Biliary elimination was very fast: 54% of the intravenous dose were biliarily eliminated within 2 h, essentially as a conjugated form. For both i.v. and p.o. routes, the blood kinetics were biexponential. Intravenous administration led to elimination half-lives of 1.36 h and 0.75 h for the first phase and 38.6 h and 56.5 h for the second one for males and females, respectively. After oral administration, rebounds corresponding to the presence of enterohepatic cycle or metabolites were observed. Thus, the determination of half-lives was not possible. Slight but significant differences of some pharmacokinetic parameters were observed between genders. The results obtained during the protein binding study corresponded to the BM 113 metabolite known as BM 212. The free fraction corresponded to 55.5%. Tissular concentrations showed a rapid distribution of 3H-BM 113 followed by a slow elimination. In most of the tissues, the decrease was biexponential. The organs containing most of the radioactivity were those of the intestinal tract and the liver. Other tissues presented concentrations close to those of plasma. Lipidic tissues, showing low BM 113 concentrations, presented a slower elimination, probably related to the high lipophilicity of molecule.
Pharmacokinetics, metabolism and bioavailability of the new anti-allergic drug BM 113. Part II: Pharmacokinetics in primates after repeated oral or single intravenous administration.
The pharmacokinetics of BM 113 (1-(benzhydryloxyethyl)piperidino-4-ethylacetate, CAS 115313-90-1; BM 113 maleate: CAS 115313-91-2) was studied using 3H-BM 113 in the Cynomolgus primate. Oral repeated administration of 0.75 mg/kg was performed on 8 days. 40 days after the oral treatment, a single intravenous administration of 0.4 mg/kg was done. Whatever the administration route, the radioactivity excretion was essentially urinary (about 60%) and most of the radioactivity was excreted within the first 24 h. The faecal elimination was low, about 10% of the administered dose. 40 days after the treatment, some radioactivity was already present in the urine. For this reason, the excretion balance ranged from 70 to 83% of the dose. The elimination half-life of 3H-BM 113 was long, about 80 h.
Pharmacokinetics, metabolism and bioavailability of the new anti-allergic drug BM 113. Part III: Pharmacokinetics, metabolism, dose dependency and gender effect after single or repeated administration to human healthy volunteers.
A new anti-allergic drug, BM 113 (1-(benzhydryloxyethyl)piperidino-4- ethylacetate, CAS 115313-90-1; BM 113 maleate: CAS 115313-91-2), with a piperidinic structure, showing anti-histaminic properties was studied after administration to healthy human volunteers. The focus was on the pharmacokinetics, the metabolism, the dose dependency and gender differences of the pharmacokinetic parameters of BM 113 and its main desacetylated metabolite, BM 212. Unchanged BM 113 was not recovered in plasma or in urine. The elimination of the radioactivity was essentially urinary with about 81% recovered within 24 h. The elimination was completed with 97% of the administered dose recovered after 120 h. HPLC dosage of BM 212, using a specific method, showed that BM 212 represented 62% of the urine radioactivity. The plasma profile of radioactivity was characterized by two decreasing phases with respective half-lives of 3.71 +/- 0.66 h and 24.67 +/- 25.01 h. A dose dependency study realised with 20, 40, 60 and 80 mg oral doses administered to 8 healthy volunteers has proven the linearity of the pharmacokinetics of BM 212 in the studied range. BM 212 disposition after single and repeated BM 113 oral doses in a 14-day study did not vary and permitted to conclude that no auto-induction or auto-inhibition phenomenon was involved. No significant difference between men and women was observed. The concentration profile was mono or biexponential, depending on the subject but whatever the gender. An inter-individual variability appeared for both sexes and caused some variations in the pharmacokinetic parameters.
Microdialysis of melatonin in the confluens sinuum of the rat following quantification by gas chromatography-mass spectrometry in the negative chemical ion mode.
In this study, an original surgical implantation technique in the confluens sinuum via the superior sagittal vein was developed to quantify melatonin secretion by the pineal gland. Melatonin (CAS 73-31-4) was determined using gas chromatography couples to negative ion chemical ionisation mass spectrometry following liquid extraction and derivatisation by penta-fluoropropionic acid anhydride (PFPA). The minimum detectable amount was 40 fg per injection, corresponding to 1 pg.ml-1 in dialysate. The assay was linear in the range 20-1000 pg.ml-1. This method was suitable for routine melatonin determination in dialysats of peripheral and central circulation with coefficients of variation of 11.2 and 24.6%, respectively for within and between analyses. Profiles of melatonin concentration were obtained (n = 3 rats) over a 2-day experimentation with a slowly diminution of the filtration capacity of the probe during the second day. The nocturnal concentrations of melatonin in the confluens sinuum dialysat ranged from 1003.9 to 2345 pg.ml-1 in the dialysat, indicating wide interindividual variations in the melatonin levels.
The roles of P-glycoprotein and intracellular metabolism in the intestinal absorption of methadone: in vitro studies using the rat everted intestinal sac.
Methadone is used as a treatment for opiate detoxification in methadone maintenance programs. Intra- and inter-patient variations in methadone bioavailability have been observed after oral methadone treatment and this makes it difficult to predict a dosing regimen. Intestinal absorption and metabolism could explain these variations. The in vitro gut sac model was used to study the intestinal absorption of methadone, and it confirmed that methadone is a substrate for P-glycoprotein. The transport of methadone was increased in presence of P-gp inhibitors verapamil and quinidine. The appearance of a major metabolite of methadone, 2-ethylidene-1, 5-dimethyl-3, 3-diphenyl pyrrolidine (EDDP) in the gut sac contents also demonstrated the existence of intestinal metabolism of methadone.
Gastrointestinal absorption of drugs: methods and studies.
Physico-chemical descriptors of drug molecules are often not adequate in predicting their oral bioavailability. In vitro methods can be useful in evaluating some of the different factors contributing to bioavailability. While physical parameters such as drug solubility may effect oral bioavailability, in most cases, the major determining factors are likely to be metabolism, and absorption at the intestinal level. Metabolism may be preabsorptive, as with peptides, or during absorption, particularly as a result of the activity of the intracellular enzyme CYP3A4. Absorption may be transcellular (membrane diffusion, carrier-mediated, endocytosis) or paracellular, while p-glycoprotein activity in the apical cell membrane may limit bioavailability by expelling drugs from the mucosal cells. Knowledge of the absorption mechanism is important in determining formulation strategies. The different in vitro techniques used to study absorption have advantages and disadvantages. Ussing chambers can be useful to measure bidirectional transport, but most studies use simple salt media, and full tissue viability is doubtful. Caco-2 cell monolayers are human cells, but the system is static, and gives very low rates of transport, and exagerated enhancement of the paracellular route compared with small intestine. The rat everted gut sac incubated in tissue culture medium maintains tissue viability and gives reliable data, although it is a closed system. In situ perfusion gives no information on events at the cellular level, and absorption may be reduced by anaesthesia and surgical manipulation. In vivo perfusion in man, with multichannel tubes, gives valuable data, but is not practical for screening. Pharmacokinetic modelling can also give useful data such as the existence of different absorption sites. Permeability values from the literature show that for small hydrophilic molecules, which pass by the paracellular route, the improved everted sac gives values close to those for humans, while values with Caco-2 cells are orders of magnitude lower.
[Continuous versus intermittent cefepime infusion in critical care. Preliminary results].
The bactericidal activity of beta-lactams is time-dependent, and the time spent above the MIC (T > MIC) is the best predictor of efficacy. A prospective, randomized, open-label study was conducted in intensive care unit (ICU) patients with gram-negative rod infections to compare the efficacy of cefepime given as a continuous versus an intermittent infusion. Of the 18 patients included to date, 14 had severe pneumonia and four bacteremia. All patients received amikacin, 15 mg/kg/d, and cefepime, 4 g/d. Patients were randomized to cefepime administration as a continuous infusion (Group 1, n = 9) or as an intermittent infusion (Group 2, n = 9, 2 g every 12 h). No significant differences were found between the two groups for age, sex, initial infection, IGS II score (46 vs 48, NS) or the MIC of the gram-negative organism. Mechanical ventilation and hospital stay durations, recovery rates, and pharmacokinetic parameters (24-h AUIC, 12-h AUIC, T > MIC, and T > 5 x MIC) were compared in the two groups using the chi-square and Mann-Whitney tests. P values < 0.05 were considered statistically significant. There were no significant differences for mechanical ventilation duration, recovery rate, hospital stay duration (34 vs 36 days, NS), 24-h AUIC (624 vs 473, NS), or the 12-h AUIC (235 vs 238, NS). There were two interesting findings: T > MIC was significantly (P < 0.05) higher in Group 1 (23.84 +/- 0.2) than in Group 2 (20.7 +/- 3), and T > 5 x MIC was also significantly (P < 0.01) higher in Group 1 (23.61 +/- 0.6) than in Group 2 (16.6 +/- 6). Although clinical outcomes were similar in the two groups, it is reasonable to assume that the longer time spent with a cefepime level above the MIC in the continuous infusion group was associated with a more stable bactericidal effect.
Pharmacokinetics of low molecular weight dermatan sulphate (desmin) in different cohorts of patients.
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Population pharmacokinetics of total and unbound etoposide.
A population pharmacokinetics study using the NONMEM program was undertaken to determine the effects of different covariates on the pharmacokinetic parameters of etoposide. A total of 1,044 plasma etoposide concentrations were determined by high-performance liquid chromatography (HPLC) in 100 patients (pts; 75 men and 25 women aged 25-85 years) treated for various tumor types with i.v. (57 pts) or oral (43 pts) etoposide. For 67 pts, etoposide plasma protein binding was determined by equilibrium dialysis; the unbound fraction ranged from 4% to 24%. A linear two-compartment model with first-order absorption (for oral dosing) accurately described the concentration versus time data. The central and peripheral volumes of distribution were significantly correlated with the body surface area [Vc (L) = 5.5 x BSA (m2) and Vp = 4.1 x BSA], but even after BSA had been taken into account, the interindividual variability of the two volumes remained high (34% and 57%, respectively). The clearance (CL) was not correlated with the following covariates: age, BSA, sex, height, and levels of serum bilirubin and liver enzymes. The final regression model for CL was CL (ml/min) = 49.8 x (1 - 0.009 x PRO) x WT/Scr + 33.8 x (1 - 0.29 x META) x (1 - 0.012 x ALB), where ALB, PRO, WT, and Scr, respectively, were albuminemia, proteinemia (g/l), weight (kg), and serum creatinine (microM) and META = 1 if the patient had liver metastases (otherwise, META = 0). The interindividual variability in CL (mean value 30 ml/min) decreased only from 32% to 26% when these covariates were taken into account. The mean oral bioavailability was 66%, showing an interindividual variability of 37%. The plasma clearance of the unbound fraction was strongly and negatively correlated with Scr but was not dependent on either PRO or ALB. These data show that modifications in PRO levels do not directly affect plasma exposure to unbound etoposide. This analysis makes possible the rational consideration of modifications of covariates such as Scr in etoposide dosing. This population data base will constitute the prerequisite for adaptative control with feedback dosing for continuous oral administration of etoposide.
Local identifiability for two and three-compartment pharmacokinetic models with time-lags.
In this paper, we show that time-lags between compartments in a 2 and 3 compartment pharmacokinetic model may be taken into account but that separate identification for model parameters and for time-lags would not be suitable. Furthermore, it may happen that a time-lag model is locally identifiable while the corresponding model without delay is not. For two-compartment delayed models, with only one observation, it is not necessary to have two different inputs contrary to the case without time-lag. Both the Laplace transformation and a Jacobian matrix are used in an identifiability study. For all two-compartment models we have investigated which kind of parameters or lags are identifiable from amount (Q) or concentration (C) measures.
Clinical pharmacokinetics of acamprosate.
Acamprosate is a new psychotropic drug used in the treatment of alcohol (ethanol)-dependence. Recent studies suggest that acamprosate inhibits neuronal hyperexcitability by antagonising excitatory amino acids. It is available as a 333 mg enteric-coated tablet, with a recommended dosage of 1.3 g/day for patients with a bodyweight < 60 kg and 2 g/day for patients with a bodyweight > or = 60 kg. Treatment with higher dose strength tablets 2 x 500 mg twice daily is bioequivalent to treatment with the 2 x 333 mg 3 times daily dosage regimen. Acamprosate is absorbed via the paracellular route in the gastrointestinal tract. Absorption is rapid but limited after oral administration. At steady-state, acamprosate has a moderate distribution volume of about 20L. Acamprosate is not protein bound or metabolised. Half of the elimination of acamprosate occurs as unchanged acetyl-homotaurine in urine, the other half might be eliminated by biliary excretion. The administration of the enteric-coated tablets showed a flip-flop mechanism with a terminal elimination half-life 10-fold higher than the 3-hour half-life reported after intravenous infusion. During repeated oral administration of 666 mg 3 times daily, steady-state is reached after 5 to 7 days and leads to plasma concentrations ranging from 370 to 650 micrograms/L. The pharmacokinetics of acamprosate administered as an enteric-coated tablets are time- and dose-independent, and its accumulation ratio is about 2.4 at steady-state. Acamprosate disposition does not differ between males and females. The pharmacokinetics of acamprosate are not modified in patients with hepatic insufficiency or chronic alcoholism. In contrast, renal insufficiency influences the elimination of acamprosate and it is, therefore, contraindicated under such circumstances. Interaction studies have confirmed that when acamprosate is concomitantly administered with food, the amount absorbed is decreased. When combined with diazepam, disulfiram or alcohol, the pharmacokinetic disposition of acamprosate is not modified. Acamprosate does not influence the kinetics of diazepam, alcohol or imipramine and its metabolite desipramine.
Enterohepatic recirculation of the new antihypertensive drug UP 269-6 in humans. A possible model to account for multiple plasma peaks.
Following a single dose of a new antihypertensive drug, UP 269-6 (5-methyl-7-propyl-8-[(2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]-1,2,4-triazolo[1,5-c]pyrimidin-2(3H)-one, CAS 148504-51-2), to 12 healthy volunteers, the plasma levels showed at least two secondary peaks. To explain this observation, the data were fitted to a new compartmental model of enterohepatic recirculation, without using a numerical method. Most subjects exhibited two cycles of recirculation. The amount of drug involved in each recirculation was calculated and the AUCs compared. The drug showed high biliary excretion and reabsorption.
Pharmacokinetics, protein binding and metabolic profile of 3H-icometasone enbutate following intravenous, oral and intratracheal administrations to Sprague-Dawley rats.
Absorption, distribution and excretion of 3H-icometasone enbutate (9 alpha-chloro-11 beta,17 alpha,21-trihydroxy-16 alpha-methylpregna-1,4-diene-3,20-dione, 17-butyrate, 21-acetate, CAS 103466-73-5 CL09) were studied in male and female Sprague-Dawley rats after a single dose administration by intravenous (1 mg/kg), oral and intratracheal (2 mg/kg) routes. The metabolic profile after the different routes and protein binding were also determined. Independent of the route, the radioactivity was mainly excreted in faeces. Less than 10% of the dose were excreted in urine. The majority of the administered doses was recovered within 24 h postdose, and the total recovery of the doses administered was obtained. After oral and intravenous administration to bile-duct cannulated rats, most of the radioactivity was excreted in the bile (80% of the administered dose) and some radioactivity was found in the faeces. It can thus be concluded that some intestinal secretion occurred. After oral administration, mean maximum blood concentrations were obtained about 0.75 h postdose. For the intratracheal route, the radioactive dose administered was too low to determine precise blood pharmacokinetic parameters. However, the distribution study results allowed us to conclude that the drug was absorbed first from the lungs and then from the gastrointestinal tract. Immediately after the intravenous injection, the liver, the kidneys, the small intestine and its contents and the carcass presented the highest levels of radioactivity. 168 h postdose, low radioactivity was still measurable in these organs. In other tissues, the radioactivity decreased reaching the limit of quantification 72 h postdose. After oral administration, the maximum concentrations were observed 1 h after administration in the liver, the small intestine and its contents. Then the radioactivity decreased in most of the tissues but a slight increase at 72 and/or 120 h postdose was noted in large intestine contents, carcass, lungs, eyes. After intratracheal administration, the maximum radioactivity was observed in lungs and trachea. A few minutes later the radioactivity reached the gastrointestinal tract. The protein binding study showed a saturable binding in rat and human plasma without notable differences between the two species. The binding on human serum albumin was shown to be non saturable with a total binding capacity of 7.48 +/- 1.83 mumol/l, suggesting that other proteins were involved in CL09 binding. This binding was demonstrated to be reversible. CL09 was extensively metabolized since no unchanged CL09 was recovered in bile or urine and at least nine metabolites have been detected. The profiles seemed to be different according to the route of administration.
Blood and cerebral concentrations of the new potential analgesic UP 26-91 measured in vivo by microdialysis after toxic doses.
The concept of proportionality between the pharmacological effects of drugs and their dosage has been questioned since the discovery of saturable phenomenon for some drug dispositions, either during their absorption or their elimination. Such saturation may also occur during the distribution phase in the tissues. This phenomenon, however, is often difficult to demonstrate and microdialysis is a powerful technique to assess precise changes in drug concentrations in tissue. This technique has been used to compare brain and blood concentrations of a potential analgesic, UP 26-91 (3-¿[2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl]thio¿ -1,2,4-triazolo[4,3-a]pyrioline, citrate salt, CAS 115762-17-9 for the base), at different intravenous doses. Microdialysis probes were surgically implanted in the cerebral cortex and the jugular vein of male Sprague-Dawley rats (about 350 g). A single dose of radiolabelled 14(C) UP 26-91 mixed with unlabelled drug was injected into the animal's tail vein. Three doses of drug (2.5, 12.5 and 22.5 mg.kg-1) were tested, with three rats for each dose. All the doses consisted of the same amount of radiolabelled product, used as a tracer, supplemented by the amount of non-radiolabelled UP 26-91 necessary to reach the desired concentration. The rats were conscious, freely moving and had free access to food and water. Microdialysis samples were collected at the rate of 1 microliter.min-1, and sampled every 15 min for 16-17 h. The two highest doses were in the range of those used for toxicological studies. Blood UP 26-91 radioactivity concentrations were superimposable independent of the dose. Thus, it can be concluded that there was a linear relationship between blood concentrations and administered doses. By contrast, the brain concentration for the highest administered dose was statistically higher than the two others (p < 0.05), which demonstrated that UP 26-91 exhibited a non-linear pharmacokinetics in the brain. It is therefore likely that a saturable transport mechanism occurs across the blood-brain barrier. This study demonstrates that blood toxicokinetics may not correctly reflect tissue exposure to a drug.