Delayed elimination of enoxaparin in patients with chronic renal insufficiency.
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Adult↗
Biomedical subjects
G Houin
Publications and source records attributed to G Houin.
Simultaneous pharmacokinetic modeling of a drug and two metabolites: application to albendazole in sheep.
Albendazole pharmacokinetic parameters were determined in lambs after iv, oral, and intraruminal single administrations. The parent drug and two metabolites, albendazole sulfoxide and albendazole sulfone, were simultaneously determined in whole blood, plasma, and urine using an HPLC method. The parent drug was only recovered in plasma when injected intravenously. For other routes, only the two metabolites were detectable; they were present in red blood cells and plasma at equal concentrations. The pharmacokinetic parameters were determined by using compartmental models which simultaneously described the two oxidative steps and the urinary excretion of the sulfoxide derivative. Dose-dependent pharmacokinetics was studied in the dose range 0.95-3.8 mg/kg. The results showed that clearance remained constant within the tested dose range since the area under the curve normalized to the dose was similar in the cases of sulfoxide and sulfone metabolites, whatever the route of administration. The drug appeared to be extensively metabolized in the body regardless of the route of administration. Sulfoxidation probably took place in liver, but other tissues seemed to be responsible for the formation of the sulfoxide which has been described as the major anthelmintic derivative of albendazole.
Administration, Oral↗
Pharmacokinetic modeling of plasma and cerebrospinal fluid methotrexate after high-dose intravenous infusion in children.
A pharmacokinetic study was performed in plasma and cerebrospinal fluid (CSF) of patients suffering from brain tumors to describe the disposition of methotrexate. An open three-compartment model was developed to fit together the data obtained in plasma and CSF. The pharmacokinetic parameters obtained by the model agreed with those obtained with classical analysis and the fitting correctly depicted the plasma and CSF concentration decays. According to the results, such a model could be applied to other anticancer drugs.
Adolescent↗
Chronopharmacokinetics of doxorubicin in patients with breast cancer.
The chronopharmacokinetics of doxorubicin (DOX) has been studied in 18 patients suffering from breast cancer. They received combined chemotherapy including DOX (50 mg/m2 as an iv bolus), given at two different times (09.00 h or 21.00 h). The two randomized courses of the protocol were given to each patient at a four week interval. The total body clearance (CL) of DOX was significantly decreased when the drug was administered at 21.00 h, resulting in a longer elimination half-life and an increase in AUC. The renal clearance of DOX did not differ at the different times of administration, and it appears that the decrease in CL was related to a change in hepatic blood flow. The volume of distribution of the drug was not changed.
Adult↗
Pharmacokinetics of ampicillin and pentobarbital in the course of subclinical fascioliasis in sheep.
Pharmacokinetics of two common veterinary drugs, ampicillin and pentobarbital, were determined in sheep before and four, eight, 12, 17 and 21 weeks after infestation of animals by an oral administration of 150 metacercariae of Fasciola hepatica. The parasite infestation was ascertained by clinical observation of the animals. The pharmacokinetics of ampicillin were not significantly affected by the liver parasitism but the disposition of pentobarbital changed. A significant increase in elimination half-life (around 180 per cent), volume of distribution (130 per cent) and mean residence time (154 to 170 per cent) was observed in sheep infected by the parasite for four to 12 weeks. In these animals, duration of narcosis caused by pentobarbital was prolonged 1.8-fold. The results suggested that both reduced elimination of pentobarbital and impaired distribution of the drug would be responsible for the prolonged duration of narcosis in infected animals.
Ampicillin↗
Relationship between loading dose and infusion rate to achieve any fraction of the steady-state level in any compartment model.
When a drug is infused at a constant rate K0, the time necessary for the concentration to reach a satisfying threshold of effectiveness may be too long. To achieve this level faster, it is useful to give simultaneously a dose D, of the same drug by intravenous injection. This paper proposes the calculation, as a function of K0 and model parameters, of the loading dose D necessary to reach, in a time T, any fraction of the asymptotic value of the amount of drug in a compartment receiving a constant rate infusion, for any n-compartment model. As an example, the expression of D for mammillary and catenary pharmacokinetic models is derived.
Body Fluid Compartments↗
Teniposide and cisplatin given by intraperitoneal administration: preclinical and phase I/pharmacokinetic studies.
Cisplatin and teniposide given by intraperitoneal (IP) route exert a synergistic therapeutic effect against ascitic P388 leukemia in mice. As single agents, they display different dose-limiting toxicities and favourable pharmacokinetic characteristics in IP phase I trials. We administered cisplatin (fixed dose: 200 mg/m2) and teniposide (escalating doses) by IP route without dwell-time to investigate the toxicity, pharmacokinetics and clinical activity of this 2-drug combination. Nine patients received a total of 14 courses. Myelosuppression, nausea and vomiting were the most frequent toxicities. Leukopenia was the dose-limiting toxicity. The maximum tolerated dose of teniposide was 100 mg/m2 when administered with a fixed dose of 200 mg/m2 cisplatin. Pharmacokinetic analysis showed that the main parameters of both cisplatin and teniposide in the peritoneum and in the plasma were not modified when the drugs were combined. It appears that a pharmacodynamic interaction exists between cisplatin and teniposide which results in increased hematologic toxicity. Although an objective response has been observed in one patient with refractory ovarian cancer, such association should not be applicable for further clinical development due to marked toxicity and the low dose of teniposide recommended.
Adult↗
Sublingual apomorphine in Parkinson's disease: a clinical and pharmacokinetic study.
The clinical response and the pharmacokinetic parameters of 3 mg subcutaneous (SC) and 30 mg sublingual (SL) apomorphine were compared in nine patients with Parkinson's disease. The magnitude of the motor responses (evaluated by tapping and walking tests and the Webster scale) was similar for SC and SL apomorphine. However, the onset to action was delayed after SL when compared with SC apomorphine. No significant difference was found in bioavailability (area under the curve: AUC) or peak plasma concentration (Cmax) between SC and SL apomorphine, whereas time to peak plasma concentration (Tmax) was shorter after SC apomorphine. Eight other patients were treated for a mean time of 4 months with SL apomorphine with a significant reduction in daily "off" hours. However, four of these eight patients developed stomatitis after some weeks of treatment. These results indicated that (a) pharmacokinetics parallel the clinical response to SL apomorphine, (b) SL apomorphine can reduce severe off periods in parkinsonian patients when used chronically, and (c) its long-term use is limited by a severe side effect (stomatitis).
Administration, Sublingual↗
Subcutaneous apomorphine increases regional cerebral blood flow in parkinsonian patients via peripheral mechanisms.
1. We have measured regional cerebral blood flow (rCBF) and motor function before and after the subcutaneous (s.c.) injection of apomorphine in parkinsonian patients deprived of their usual treatment for at least 48 h. 2. Nineteen patients, pretreated with domperidone (20 mg three times daily for 48 h), received a mean dose of 5.8 mg s.c. apomorphine. All patients switched 'on'. The mean motor score was significantly improved (-65%, P less than 0.01) but no significant change in rCBF was observed. 3. Seven other patients, not pretreated with domperidone, received a lower dose (0.3 mg) of s.c. apomorphine. No change in motor score was observed while the mean rCBF significantly increased (+12%, P less than 0.05). 4. We conclude that s.c. apomorphine increases rCBF in parkinsonian patients. This effect is independent of the central therapeutic effects of the drug. It is mediated by the stimulation of dopaminergic receptors of the cerebral vessels. These receptors are located outside the cerebral blood brain barrier and can be considered as 'peripheral' ones.
Aged↗
The pharmacokinetics of dermatan sulphate MF701 in healthy human volunteers.
1. The pharmacokinetics of dermatan sulphate MF701 were studied in 12 healthy males after administration of single intravenous bolus (200 mg), intramuscular (100 and 300 mg) and oral (1 g) doses. The study was conducted according to a within-subject crossover design in two paired blocks. 2. Plasma drug concentrations were measured using a competitive binding assay and a range of biological activity assays, including a sensitive catalysed thrombin inhibition test. 3. Following intravenous administration, plasma concentrations of dermatan sulphate determined by competitive binding assay were described by a two-compartment open model with an initial t1/2, in of 0.6 h and a t1/2,z of 7.5 h. Biological activity assays were insufficiently sensitive to detect the second phase, and therefore yielded apparent monoexponential kinetics. 4. After intramuscular injection the apparent bioavailability of dermatan sulphate was 16-20%. Plasma drug concentrations increased in proportion to dose when measured by competitive binding assay. Low concentrations persisted for more than 24 h at the higher dose, and these may prove therapeutically relevant on chronic administration. 5. We confirm that dermatan sulphate is the only glycosaminoglycan known to generate significant plasma concentrations following oral administration. Oral bioavailability was estimated to be 7%.
Adolescent↗
Pharmacokinetics of a low molecular weight heparin (Fraxiparine) in various stages of chronic renal failure.
This study investigates the pharmacokinetics of a low molecular weight heparin (Fraxiparine) after a single bolus intravenous injection of 100 antifactor Xa IC U.kg-1 in 3 groups of patients affected by chronic renal insufficiency of various severity: group A (n = 7) was composed of hemodialyzed patients; groups; B (n = 7) had a creatinine clearance ranging from 10 to 20 ml.min-1 and group C (n = 5) from 30 to 50 ml.min-1. There was no significant difference between the pharmacokinetic parameters determined in the 3 groups of patients and no correlation between these parameters and the creatinine clearance. However, when compared to the values established in a group of 12 healthy volunteers, the half-life of disappearance of the antifactor Xa activity was significantly prolonged. Therefore it is advised to monitor antifactor Xa activity in patients affected by chronic renal insufficiency of any severity to avoid a possible accumulation phenomenon.
Adult↗
Decrease in albendazole sulphonation during experimental fascioliasis in sheep.
1. The in vivo S-oxidation of albendazole was measured from the pharmacokinetic profile of albendazole sulphoxide and sulphone determined in young male sheep receiving oral albendazole (1.9 mg/kg). Studies were carried out before, and each month after, oral infestation by 150 metacercariae of Fasciola hepatica. 2. Parasitic pathology was ascertained by clinical observation of animals, and the increase in plasma antibodies directed against liver flukes. 3. Rate of conversion of sulphoxide to sulphone and rate of sulphone elimination, were respectively decreased by 47% and 87% at week 8 post-infection, whereas significant increases in the area under plasma sulphone concentrations versus time curve and mean residence time, occurred 4-12 weeks following the infestation. 4. A 58% decrease in albendazole sulphonation was demonstrated in liver microsomal preparations obtained from 8-week-infected sheep, while there was no change in the FAD-directed sulphoxidation of albendazole. 5. The transient impairment of albendazole sulphonation could be related to the decrease in liver microsomal cytochrome P450-dependent monooxygenases observed in sheep with a similar parasitic pathology.
Administration, Oral↗
Protein binding of methotrexate to human albumin and serum. A first derivative spectroscopic analysis.
Usual methods allowing the measurement of the free concentration of a drug in serum, i.e. equilibrium dialysis, ultrafiltration and ultracentrifugation, are generally based on a physical separation of the bound and free fractions. During this, variations or errors may occur which are probably at the origin of the variability of the previously published results for methotrexate (CAS 59-05-2). In order to verify these results as well as to experience a technique recently applied to rifampicine the first derivative spectroscopic analysis was used to estimate the bound and free fractions of methotrexate in human serum and serum albumin (HSA). Free drug concentrations were measured at 377 nm and the bound form at 372.5 nm. In human serum, bound methotrexate was 54.1% on average for total concentrations ranging from 10(-5) mol/l to 10(-3) mol/l, without any saturation. With HSA, a saturation occurred. Scatchard analysis showed one family of binding sites characterized by 2 binding sites and an affinity constant of 3200 mol/l, in mean, values close to that previously calculated using equilibrium dialysis.
Binding Sites↗
Plasma catecholamine levels and lipid mobilization induced by yohimbine in obese and non-obese women.
Oral yohimbine administration (0.2 mg/kg) induced lipid mobilization (increase in plasma non-esterified fatty acids, NEFA) in fasting non-obese women (body mass index BMI = 20.2 +/- 0.5, age 35.5 +/- 2.7 years) without significant action on plasma glucose, insulin levels, heart rate or blood pressure during the time-course of the experiment (240 min). Plasma norpinephrine (but not epinephrine) concentrations were increased (100 percent) after oral yohimbine administration. Oral administration of propranolol (40 mg, 60 min before yohimbine) reduced the lipid-mobilizing action of yohimbine (70 percent) during the 60 min following its administration and then totally suppressed its effect until the end of the experimental period (180 min). In fasting obese women (BMI = 36.4 +/- 2.1, age 37 +/- 3.6 years), yohimbine provoked an increase in plasma NEFA levels which was not markedly different from that observed in non-obese subjects. It had no significant effect on plasma glucose, insulin levels, heart rate or blood pressure. Plasma norepinephrine increased in the same proportions. The lipid-mobilizing effect of yohimbine in women is mainly attributable to the increase in synaptic norepinephrine with a resultant increment in lipolysis by beta-adrenergic agonism. In the standard fasting conditions (12 hours) the blockade of the antilipolytic fat cell alpha 2-adrenoceptors seems to be a minor component of the lipomobilizing effect of yohimbine. Morever, when compared with non-obese women, the lipomobilizing effect of yohimbine is not enhanced in obese women.
Administration, Oral↗
Human pharmacokinetics and pharmacodynamics of MF 701 dermatan sulfate administered by continuous intravenous infusion.
The pharmacokinetics and haemostatic effects of MF 701 dermatan sulfate (DS) administered by i.v. infusion were studied in 11 healthy volunteers. Each subject received 0.6 mg kg-1 h-1 MF 701 for 10 h. DS plasma concentrations were measured by a chromogenic assay based on the catalysis of thrombin inhibition by HCII. DS plasma levels followed a single compartment pharmacokinetic model, with a half-life of 1.28 +/- 0.46 h, a plasma clearance of 2.75 +/- 0.46 l/h and a volume of distribution of 4.92 +/- 1.36 1 (means +/- SD). Steady-state was reached 3 to 6 h after infusion started. The maximal DS plasma concentration was 16.4 +/- 5.7 micrograms/ml. Maximal APTT prolongation over pre-infusion values was 42 +/- 7%; TCT performed with bovine and human thrombin was prolonged by 16 +/- 7% and 83 +/- 35% respectively. No anti-IIa or anti-Xa activities were detected by chromogenic tests. The treatment was well tolerated. The pharmacokinetics of MF 701 infusion are consistent with those previously described after i.v. bolus administration. The infusion of MF 701 allows fast achievement and steady maintenance of elevated DS plasma concentrations.
Adolescent↗
Pharmacokinetics of prednisolone in children with the nephrotic syndrome.
The aim of this study was to establish whether the criteria for the clinical effectiveness of steroids are correlated with the pharmacokinetics of prednisolone in children treated with prednisone during an attack of idiopathic nephrotic syndrome (INS). Thirteen patients with nephrosis were included. Prednisolone, prednisone and cortisol levels were measured using a specific high-performance liquid chromatography assay after an oral dose of 1 mg/kg body weight of prednisone taken at the onset of the disease. All the pharmacokinetic parameters, including the conversion of prednisone to prednisolone were similar to the data already published in children with INS. No correlation was found between the values of pharmacokinetic parameters and criteria of clinical effectiveness. Hypo-albuminaemia was significantly correlated with the area under the plasma-concentration curve but not with the elimination half-life of prednisolone. Moreover, the prednisolone elimination half-life correlated with the urinary excretion of 17-hydroxycorticosteroids achieved in the first 6 h. The present study suggests that routine measurements of prednisolone kinetics do not help when assessing the treatment of children with INS.
17-Hydroxycorticosteroids↗
Pharmacokinetics and toxicity of two modalities of etoposide infusion in metastatic non-small-cell lung carcinoma.
The pharmacokinetics and toxicity of two schedules of etoposide administration were studied in 19 patients suffering from metastatic non-small-cell lung cancer. Ten subjects received a 72-h continuous venous infusion (CVI) of 360 mg/m2 etoposide, and nine were given a daily dose of 120 mg/m2 for 3 consecutive days. In the two groups 80 mg/m2 cis-diamminedichloroplatinum (II) (CDDP) was infused on day 1. With CVI, the steady-state plasma concentration was reached 12-24 h after the start of the treatment. The plasma elimination rate showed a biexponential decay curve in both groups. No significant difference between total body clearance and the beta-phase volume of distribution was noted between the two modalities of administration. No relationship was found between biological and pharmacokinetic parameters.
Aged↗
Analytical study of open four compartment pharmacokinetic models: concentrations, area under curves, mean residence times.
The analytical expressions for drug concentrations in each of the four compartments of different pharmacokinetic models, following any type of drug administration, are obtained from the transfer and elimination coefficients. In addition, areas under concentration curves and mean residence time of the drug, in a given compartment or in the whole system, are derived.
Administration, Oral↗