Armand Frydman

Low-molecular-weight heparins: an overview of their pharmacodynamics, pharmacokinetics and metabolism in humans.

Low-molecular-weight heparins (LMWHs) comprise a group in the class of antithrombotic medications, a class headed by unfractionated heparin (UFH). The LMWHs, with mean molecular weights of 4.0-6.0 kD, differ in their individual manufacturing processes, the distribution of their fragment molecular weights, their in vitro potency (anti-Xa, antithrombin and anticoagulant activities) and, consequently, in their biodynamic patterns, recommended dose regimen, and efficacy/safety ratio. Their drug disposition profiles have been evaluated using two significant markers of their pharmacodynamic activity, namely anti-Xa and anti-IIa activities. Since they are mainly administered subcutaneously, then compared to UFH, they are almost completely absorbed (F > or = 90%) and, in contrast to UFH, those for which data are available in the literature exhibit linear pharmacokinetics with proportionality between anti-Xa (and anti-IIa in some cases) plasma concentration and dose, and stationary distribution volume and clearance processes when the dosage is increased. Their distribution volume is close to the blood volume, they are partially metabolized by desulphatation and depolymerization, but urinary excretion of anti-Xa activity for enoxaparin, dalteparin and nadroparin, all given at doses for prevention of venous thrombosis, is between 5 and 10% of the injected dose. However, these LMWHs differ in the extent of their non-renal clearance, resulting in different apparent elimination half-life values and relative apparent bioavailability. When considering certain at-risk situations, using doses for preventing thromboembolism, the LMWHs do not significantly cross the placenta of pregnant women and their excretion profiles are only slightly altered in severe (endogenous creatinine clearance less than 15 ml/min) renal disease patients when given at doses recommended for prevention of venous thromboembolism. Because of the differences among LMWHs, the clinical profile of a given LMWH cannot be extrapolated to another one or generalized to the whole LMWH family.

Determination of Taxotere in human plasma by a semi-automated high-performance liquid chromatographic method

A rapid, selective and reproducible high-performance liquid chromatographic (HPLC) method with ultraviolet detection was developed for the determination of the anti-cancer agent Taxotere in biological fluids. The method involves a solid-phase extraction step (C2 ethyl microcolumns) using a Varian Advanced Automated Sample Processor (AASP) followed by reversed-phase HPLC. The validated quantitation range of the method is 10-2500 ng/ml in plasma with coefficients of variation < or = 11%. The method is also suitable for the determination of Taxotere in urine samples under the same conditions. The method was applied in a phase I tolerance study of Taxotere in cancer patients, allowing the pharmacokinetic profile of Taxotere to be established.

Pharmacokinetics of Sparfloxacin in Humans After Single Oral Administration at Doses of 200, 400, 600, and 800 mg

The pharmacokinetics of sparfloxacin at oral doses of 200, 400, 600, and 800 mg were studied in 12 healthy volunteers in a randomized double‐blind crossover study. Each dose administration was separated by a 1‐week washout period. Plasma and urine samples were collected up to 120 hours postdosing, for determination of free and total (free plus glucurono‐conjugated) sparfloxacin levels by high‐performance liquid chromatography assay and ultraviolet detection. Mean Cmax values ranged from 705 ± 158 to 1966 ± 620 ng/mL for the 200 to 800 mg doses, at median tmax ranging from 4 to 5 hours. A slight decrease of sparfloxacin bioavailability with increasing dose was observed because AUC was 87% to 88% of the expected area when the dose was doubled. The elimination half‐life values were constant over the dose range (with values ranging from 18 to 21 hours) as well as the renal clearance. The metabolic ratio conjugated/free drug was not modified by increasing dose.

Total and free ketoprofen in serum and synovial fluid after intramuscular injection

Free and total ketoprofen levels in serum and synovial fluid were determined in 37 patients after a single intramuscular injection of ketoprofen, 100 mg. Free drug was separated by equilibrium dialysis. Ketoprofen was assayed by HPLC. Ketoprofen penetrated into the joints rapidly and significant concentrations were found at 15 minutes. The equilibrium time was about 3½ hours. The AUC for total ketoprofen was greater in serum than in synovial fluid. On the other hand, the free fraction AUC in the serum and synovial fluid were quite similar. The mean residence time in the joint was about three times that in the systemic circulation. Ketoprofen was strongly bound to proteins and the percentage of free ketoprofen was not significantly different between serum and synovial fluid. These results provide a possible explanation for duration of the therapeutic effect of ketoprofen despite the short elimination half‐life from the serum.

Simultaneous determination of zopiclone and its two major metabolites (n-oxide and n-desmethyl) in human biological fluids by reversed-phase high-performance liquid chromatography

A high-performance liquid chromatographic method has been developed for the simultaneous determination of zopiclone and its main metabolites (N-oxide and N-desmethyl derivatives) in biological fluids. After selective extraction (dichloromethane-2-propanol) these compounds are chromatographed on a column packed with Spherisorb ODS-2 (5 micron) using monobasic sodium phosphate-methanol (45:55, v/v). The eluted compounds are measured by fluorescence detection. The limit of detection of the method is 5 ng/ml for zopiclone in plasma and urine and 10 ng/ml for its two main metabolites (coefficient of variation less than 10%). This method has been successfully applied to pharmacokinetic studies of zopiclone and its two main metabolites in healthy subjects and patients with chronic renal failure.

Influence of rifampin on the pharmacokinetics of pefloxacin

Pefloxacin and rifampin are frequently associated in the antibiotic therapy of deep‐seated, and especially bone‐located, infections. The influence of rifampin, a potent drug metabolism enzyme inducer, on the pharmacokinetics of pefloxacin was studied in a randomized crossover trial involving eight young healthy male volunteers. Every volunteer received either pefloxacin alone (period A) or pefloxacin after a 10‐day induction by rifampin (period B) given as a 900 mg daily oral dose, and both periods were separated by a 3‐week washout period. During both periods, pefloxacin was given during 3 days as a 400 mg b.i.d. oral dose (six doses) followed by a 400 mg intravenous dose on the fourth day. The kinetics of pefloxacin are significantly influenced by rifampin: The minimum (12‐hour) plasma concentration, area under the concentration‐time curve, and elimination half‐life decreased respectively from 4.26 ± 1.57 to 2.70 ± 1.00 mg/L, 78.91 ± 22.82 to 57.81 ± 16.69 mg · hr/L, 14.46 ± 3.46 to 10.08 ± 2.44 hours(p <0.05). The renal clearance of pefloxacin was unchanged, but the plasma clearance increased from 94.04 ± 39.04 to 126.82 ± 47.36 ml/min(p <0.05). The plasma clearance of N‐demethyl and N‐oxide metabolites were similar for both periods, but the cumulative renal excretion (0 to 96 hours) decreased significantly (p <0.01) for period B versus period A. This definite but moderate inductive effect of rifampin on the pharmacokinetics of pefloxacin does not suggest a dose modification of pefloxacin in therapeutic association with rifampin, but pefloxacin assay in plasma seems to be advisable.

Automated high-performance liquid chromatographic determination of spiramycin by direct injection of plasma, using column-switching for sample clean-up.

A fully automated high-performance liquid chromatographic method is described for the determination of spiramycin 1 in plasma. First, 1 ml of plasma is diluted with 1.5 ml of 4% acetonitrile containing spiramycin 2 as internal standard, and 1 ml is then injected via an automatic sampling unit. A pneumatic valve, which is remote-controlled by the programmable timer of an integrator, switches the sample, initially injected onto a precolumn for sample clean-up, to an analytical column for sample separation. This method was compared with a microbiological assay and has been successfully applied to pharmacokinetic studies on spiramycin in humans.

New electron-capture gas-liquid chromatographic method for the determination of mexiletine plasma levels in man

A method for the determination of mexiletine in human plasma by gas-liquid chromatography with electron-capture detection is described. Plasma samples are extracted at pH 12 with dichloromethane after addition of the internal standard, the 2,4-methyl analogue of mexiletine. A derivative is obtained using heptafluorobutyric anhydride; according to gas chromatography-mass spectrometry it is a monoheptafluorobutyryl compound. The minimum detectable amount of mexiletine is 5 pg. Accurate determinations of human plasma levels were performed after oral or intravenous treatment.

Comparison of the pharmacokinetics of intravenous dl-propranolol in borderline and permanent hypertension.

SummaryIn borderline and permanent hypertensives after rapid i.v. injection of dl-propranolol 0.2 mg/kg plasma levels were measured and were fitted to a two-compartment open-model. In borderline patients, characterized by a high basal cardiac output (CO), plasma levels were always lower than in permanent hypertensives. The biological half-life was reduced and the central volume of distribution, volume of distribution at pseudo-equilibrium and total clearance (TC) were markedly increased. In the overall population, there was a significant positive correlation between CO and TC. Rapid achievement of a predetermined plateau in each group constituted experimental proof of the validity of the two-compartment open-model for kinetic analysis of propranolol i.v. If kinetic parameters from permanent hypertensives were applied to borderline hypertensives a lower plateau was obtained. Thus, in so far as β-blockade is related to plasma level of propranolol, an increased intravenous dose may be required in patients with high CO.

Comparative Bioavailability Study of Cefixime Administered as Tablets or Aqueous Solution

SummaryThe relative bioavailability of cefixime was studied in 24 healthy male volunteers, with each subject receiving a single 400mg dose of cefixime administered as an aqueous solution, a 400mg tablet and two 200mg tablets, in a randomised crossover sequence. Serum and urine samples were analysed using high-performance liquid chromatography. Peak cefixime levels were achieved 3 hours after administration of the solution vs 4 hours for the 2 tablet formulations; however, the extent of absorption was only slightly improved with the solution (by 14 and 7% compared with the 1 × 400 and 2 × 200mg tablets, respectively). The 400mg and 2 × 200mg tablets were found to be bioequivalent. The pharmacokinetic profile of the 400mg cefixime tablet (mean maximum plasma concentrations of 4.4 mg/L at 4 hours, area under the concentration-time curve of 34.4 mg/L · h, and apparent terminal elimination half-life of 3.7 hours) supports the clinical evaluation of a 400mg once-daily dosage regimen for cefixime.