Effect of posture on total phenytoin plasma concentration.
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Biomedical subjects
Publications and source records attributed to F Demotes-Mainard.
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Imipramine was used to treat 18 depressed inpatients for 22 days. Imipramine 2 mg/kg/day was administered from day 0 to day 14 intramuscularly, and 4 mg/kg/day was administered orally from days 15-21. Two pharmacokinetic studies were performed, the first at the end of the intramuscular phase (day 14) and the second at the end of the oral phase (day 21). Imipramine and desipramine blood levels were measured every hour from 8 a.m. to 4 p.m. Between these two pharmacokinetic evaluations, blood levels of imipramine and desipramine were measured every morning at 8 a.m. During intramuscular administration, the parent drug imipramine predominated in the plasma and, conversely, the desmethylated metabolite predominated during oral administration. With the changeover in route of administration, the doubling of the dose kept the blood levels of imipramine equal, while desipramine increased; the sum of imipramine and desipramine also increased, and the ratio of imipramine and desipramine decreased sharply, the median ratio changing over 3 days from 1.50 (day 15) to 0.62 (day 18).
The role of fever on cefotaxime disposition was studied in ten hyperthermic patients. Each subject received intravenously 1 g of cefotaxime on two separated occasions, first when the body temperature was more than 39 degrees C then during a basal state (37 degrees C). Blood samples were taken over 12 hours and urine was collected for 24 hours after injection. After dosing cefotaxime and its metabolite by high performance liquid chromatography, the pharmacokinetic parameters were calculated, especially: plasma and renal clearance, volume of distribution at steady state, area under the curve, and elimination half-life. There is no significant difference in cefotaxime and desacetylcefotaxime disposition between these two states. Hyperthermia has no influence on pharmacokinetics of this cephalosporin.
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The steady state pharmacokinetics of oral carbamazepine in epileptic patients (n = 8) was compared before and after one week of treatment with josamycin (2 g/day). There was a small but statistically significant decrease in oral clearance of total (17%) and unbound (21.5%) drug. In spite of an unchanged AUC of 10,11-epoxide carbamazepine the ratio of metabolite to parent drug AUC was significantly decreased (20.2%). The plasma protein binding of carbamazepine and its 10,11-epoxide metabolite did not vary. The results demonstrate impairment by josamycin of the apparent clearance of carbamazepine. Care should be taken in patient receiving both carbamazepine and josamycin.
The authors, by performing in vitro perfusion on six human placentas, have studied the passage of chloroquine sulphate into the placenta. The drug levels were recorded by high performance liquid chromatography (HPLC). The placental perfusions lasted one hour and drug passage into placental tissue was low (14.21%) which seems to be due to the high degree of fixation of chloroquine on placental tissue.
The kinetics of moxalactam has been investigated in 10 subjects undergoing continuous ambulatory peritoneal dialysis (CAPD). A single 1 g dose was injected i.v. and a 1 g dose was given intraperitoneally in the CAPD fluid during a 4 h dwell-time. Moxalactam was assayed by HPLC. After i.v. injection, the serum kinetics of moxalactam were: plasma t 1/2 = 17.9 h; volume of distribution at steady-state, 0.27 l/kg; total plasma clearance, 12.8 ml/min; peritoneal clearance, 2.1 ml/min. Dialysate moxalactam concentrations rose rapidly but only 20% of the dose was eliminated by the peritoneal route. After intraperitoneal instillation, moxalactam appeared in the serum rapidly and the peak serum concentration ranged from 21 to 49 micrograms/ml after between 4 and 5 h. The absorption of moxalactam from the peritoneal space was 57 +/- 16%. The data suggest that moxalactam has bidirectional exchange characteristics through the peritoneal membrane. Instillation of moxalactam in CAPD fluid may permit rapid absorption and the appearance of a therapeutic serum concentration.
The kinetics of ceftriaxone was investigated in 8 patients without infection, who were receiving continuous ambulatory peritoneal dialysis (CAPD). Ceftriaxone 1 g was injected i.v. and 1 g was given intraperitoneally in the CAPD fluid during a 4-h dwell time. Ceftriaxone was assayed by HPLC. After intravenous administration, the kinetic parameters of ceftriaxone were: plasma t1/2, 12.3 h, total plasma clearance, 14.0 ml/min, volume of distribution at steady state 0.18 l/kg, and peritoneal clearance 0.59 ml/min. Over 72 hours only 5.5% of the dose was eliminated by the peritoneal route. After intraperitoneal administration, ceftriaxone rapidly appeared in serum; the absorption t1/2 was 1.1 h and the mean peak concentration was 38.8 micrograms/ml. The absorption of ceftriaxone from the peritoneal space was 39%. A single 1.0 g IP dose led to serum and dialysate concentrations of ceftriaxone above the minimum inhibitory concentration for susceptible pathogens for 24 hours.
The effect of two antacids on the bioavailability of paracetamol has been investigated in 12 young healthy volunteers. Following a random cross over design, each subject swallowed, on three separate occasions, one weak apart, 500 mg paracetamol alone, or together with two different aluminium hydroxide, magnesium hydroxide preparations (Dimalan and Maalox). Plasma paracetamol levels were measured by HPLC. The bioavailability of paracetamol was not altered by either antacid, but they both delayed the time to peak plasma concentration (0.85 h; 1.43 h; 1.25 h, without antacid, with Dimalan and with Maalox respectively). The peak plasma concentration was not affected by concurrent antacid administration.
Ten fasting subjects received 200 mg cimetidine orally either with water or 11 g aluminium phosphate mixture in a randomized, single dose, two-way cross-over study. Blood samples were taken for 12 h and urine was collected for 24 h. Cimetidine in plasma and urine was analysed by HPLC. There were no significant differences between the treatments with respect to peak plasma concentration, time to peak plasma concentration, area under the plasma concentration-time curve, and urinary excretion. In 12 healthy subjects the absorption of prednisolone was investigated when given alone and together with 11 g aluminium phosphate. Blood samples were taken over 16 h and prednisolone in plasma was analysed by HPLC. There were no significant differences in the values of area under curve (AUC), Cmax and tmax. The results indicate that aluminium phosphate does not reduce the bioavailability of cimetidine and prednisolone.
The authors propose an assay technique for cefotaxime and desacetylcefotaxime in the plasma and urine, using high performance liquid chromatography. The proteins are precipitated by adding propanol-2 to 100 microliter of plasma or urine. After centrifugation, the supernatant is extracted by a mixture of chloroform and isoamyl alcohol. The cephalosporins remain in the superior aqueous phase and a fraction of this phase is injected into the chromatograph. The cefotaxime, desacetylcefotaxime and cephaloridine (internal standard) are separated on a Radial Pak C 18 column by ion-binding chromatography. The mobile phase consists of a mixture of distilled water and acetonitrile (830/170, V/V) with the addition of an ampoule of Pic A (tetrabutylammonium phosphate). This rapid, specific and sensitive micro-method can be used for the assay of these antibiotics in adults and children, for therapeutic monitoring and for pharmacokinetic studies.
Theophylline, phenobarbitol, and valproic acid serum levels were measured from plasma samples using chromatographic (HPLC and GC) and by immunologic techniques using enzyme kinetics (EMIT) or fluorescence polarization (FPIA). Results of these various methods differ when examined by more stringent statistical analysis. These differences do not appear to be clinically important except possibly for valproic acid the case in employing immunologic methods as well as their rapidity render these techniques particularly useful for therapeutic surveillance.
A plasma assay for paracetamol by HPLC is described. Paracetamol is extracted with diethyl ether in the presence of an internal standard, beta- hydroxyethyltheophylline . The extracts are analysed using reversed phase chromatography (Radial Pak C18 column), the mobile phase consisting of a buffer mixture of 0.01 mol/l acetate (pH 4)-acetonitrile (920-80, v/v). The method is simple, rapid, precise and sensitive (lower level of sensitivity 0.13 mumol/l). It was used in a pharmacokinetic study in twelve volunteers.
Hyperglycemia may modify pharmacokinetics of some antibiotics as shown in the literature. We studied the influence of glycaemic levels on pharmacokinetics properties of cefoperazone in 12 type 1 insulin dependent diabetic patients. Hyperglycaemia was obtained by a reduction of one quarter of their usual insulin dosage and normoglycaemia by an artificial pancreas (Biostator GCIIS). Cefoperazone had a high protein affinity and a high biliary elimination. Pharmacokinetic study was performed during a 8 hour period following one gram intravenous bolus. We did not found any influence of glycaemic level (normoglycaemia or hyperglycaemia) on the pharmacokinetic parameters of cefoperazone.
The kinetics of chlormezanone were determined after oral administration of single (400 mg) and multiple doses (400 mg/day during 8 days) in eight young healthy male subjects. Plasma levels determination had been carried out by HPLC. After single dose administration, Cmax concentrations 4.62 +/- 0.75 mg/l were obtained (Tmax) 2.18 +/- 1.49 h after drug intake. Area under plasma concentrations time curve was 224.93 +/- 27.79 mg.h/l and terminal half-life 40.50 +/- 4.19 h. On chronic regimen, chlormezanone accumulates in the body: trough plasma concentrations are significantly increased from Day 7 (2.97 +/- 0.45 mg/l) to Day 9 (5.41 +/- 0.90 mg/l) and reach the steady state faster than it can be expected from half-life (40 hours) and dosing interval (24 hours). Elimination is faster (T1/2 beta = 37.14 +/- 3.18 h) after chronic regimen. Area under curve during dosing interval at steady state (164.19 +/- 21.70 mg.h/l) is significantly lower than the area under curve between zero and infinity in the single dose sequence (224.93 +/- 27.79 mg.h/l). These results agree with probable induction effect of chlormezanone on its own metabolism.
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