T. B. Tjandramaga

Piperacillin: Human Pharmacokinetics After Intravenous and Intramuscular Administration

The pharmacokinetics of piperacillin were studied in a total of 26 Caucasian normal male volunteers. Single intramuscular doses of 0.5, 1.0, and 2.0 g were given to three groups, each containing eight volunteers. Mean peak serum concentrations of 4.9, 13.3, and 30.2 μg/ml were assayed at 30 to 50 min, and measurable levels were present up to 4, 6, and 8 h, respectively, after dosing. Single intravenous bolus doses of 1.0, 2.0, 4.0, and 6.0 g were given to four groups of five subjects, and mean serum concentrations of 70.7, 199.5, 330.7, and 451.8 μg/ml were measured at the end of the injections. The antibiotic had a mean terminal serum half-life of 60 to 80 min after the intramuscular doses and 36 to 63 min after intravenous administrations, depending on the dose. The apparent distribution volume was 20 to 24 liters/1.73 m2, and distribution volume at steady state was 16 to 19 liters/1.73 m2. Mean urinary recovery in 24 h was 74 to 89% for the intravenous doses and 57 to 59% for the intramuscular doses. The piperacillin-creatinine clearance ratios indicated that the proportion of renal excretion of piperacillin through tubular secretion was 56 to 73%, and this was confirmed by the renal clearance data from eight volunteers receiving probenecid treatment before the piperacillin dose. Probenecid (1 g given orally before administration of piperacillin) increased peak serum concentration by 30%, terminal serum half-life by 30%, and the area under the plasma concentration curve by 60%, and it decreased the apparent distribution volume by 20% and the renal clearance of the intramuscularly administered (1 g) antibiotic by 40%. Injections of piperacillin by both parenteral routes were well tolerated.

High-performance liquid chromatographic determination of 12 antiarrhythmic drugs in plasma using solid-phase column extraction.

Summary: Monitoring of plasma concentrations of antiarrhythmic drugs may assist in individualizing dosage regimens and in assessing patient compliance. A rapid high-performance liquid chromatographic assay using solid-phase column extraction was developed for the following antiarrhythmic drugs: amio-darone, aprindine, disopyramide, flecainide, lidocaine, lorcainide, mexiletine, procainamide, propafenone, sotalol, tocainide, and verapamil. As most of the antiarrhythmic drugs are basic compounds, good adsorption on the extraction columns was obtained by alkalinization; aprindine, however, was applied at neutral pH and amiodarone at pH 3.5. After washing with water, the compounds were eluted with methanol, but amiodarone was eluted with a mixture of acetonitrile and acetate buffer at pH 5 (8/2, vol/vol). Most of the eluates were evaporated to dryness and reconstituted in the mobile phase; for amiodarone, disopyramide, and tocainide, direct injection onto the column was performed. Separation was done on a Spherisorb hexyl 5μ column (150 x 4.6 mm I.D.) and the mobile phases consisted of mixtures of acetonitrile or methanol with phosphate or acetate buffers at different pH values. Detection was performed by UV or fluorescence detector. Coefficients of variation were lower than 10% with good recovery and linearity in the expected therapeutic ranges.

Comparative pharmacokinetics of ceftazidime and moxalactam.

The pharmacokinetics of ceftazidime and moxalactam were compared after intravenous and intramuscular administration of single 1-g doses to eight healthy volunteers in a crossover study. The bioavailability of the antibiotics after administration by either route was almost complete. Both drugs had similar areas under the serum curves. Significant differences between ceftazidime and moxalactam were observed with respect to the apparent volume of distribution (18.4 and 24.1 liters, respectively), to the terminal half-life (1.6 versus 2.0 h), and to urinary recovery of the active compound (96 versus 79%). Ceftazidime was almost completely eliminated by renal excretion (greater than 96%), whereas about 20% of the moxalactam was eliminated by nonrenal mechanisms. The concentrations of ceftazidime and moxalactam in serum after a 1-g dose exceeded the concentrations required to inhibit 90% of the Enterobacteriaceae for about 8 and 10 h, respectively. The levels of ceftazidime and moxalactam in serum exceeded the 90% minimal inhibitory concentration of Pseudomonas aeruginosa for about 6 and 1 h, respectively.

Pharmacokinetic interaction between indomethacin and diflunisal

SummaryThe effect of treatment with diflunisal on the steady-state pharmacokinetics of indomethacin has been studied in 16 healthy volunteers.The steady-state plasma concentration and AUC of indomethacin were significantly increased two- to threefold during treatment with diflunisal and its total clearance and total volume of distribution were significantly decreased. The urinary recovery of total indomethacin (unchanged+glucuronides) was significantly lower during administration of diflunisal, whereas excretion of the indomethacin metabolites desmethylindomethacin and desbenzoylindomethacin and their glucuronides was not significantly altered. The results can be explained by selective inhibition of glucuronidation of unchanged indomethacin by diflunisal.The interaction appears clinically relevant as potentially dangerous side effects of indomethacin are related to its plasma concentration.

Comparative Multiple Dose Kinetics of two Formulations of Indomethacin

SummaryThe kinetics of a controlled release (CR) formulation of indomethacin 75 mg (Indocid-Retard®) given once daily was compared with a conventional 25 mg indomethacin capsule (Indocid®) given 3 times daily for 7 days, to 14 healthy volunteers, using a randomized, cross-over, multiple-dose study design. The following differences in plasma indomethacin profiles after the 2 treatments were observed: average peak concentrations (Cmax) for the CR regimen were higher and the time to peak (Tmax) was significantly delayed. Trough (pre-morning dose) plasma concentrations (Cmin) on Days 2, 5, 6 and 7 were significantly lower after the CR-formulation. No statistically significant differences between preparations for area under the plasma concentration time curve (AUC0–24h) or for renal clearance were observed. Average steady-state plasma concentrations (Cpss) on Day 7 of the multiple dose regimens averaged 0.477 and 0.427 µg/ml for the 75 mg CR once daily and the conventional 25 mg t.i.d. treatments, respectively. These results show that the bioavailability of the CR and conventional indomethacin formulations under these multiple-dose conditions was not significantly different.

Plasma concentrations and effect on testosterone metabolism after single doses of MK-0434, a steroid 5 alpha-reductase inhibitor, in healthy subjects

A four-period, two-panel, single-rising-dose study (0.1–100 mg) was conducted in healthy males to investigate the pharmacodynamics, tolerability and pharmacokinetics of MK-0434, a steroid 5α-reductase inhibitor. MK-0434 was associated with a significant reduction in dihydrotestosterone, which was maximal at 24 h and maintained through 48 h post treatment. The maximum reduction was approximately 50 % and occurred at all doses above 5 mg (10, 25, 50 and 100 mg).MK-0434 appeared to have no effect on serum testosterone at these single doses. Rising single doses of MK-0434 were associated with an increase in Cmax and AUC but the changes were less than proportional to dose, most likely due to nonlinear absorption. MK-0434 given in single doses up to 100 mg was without significant adverse effects in healthy male volunteers. In summary, MK-0434 is a well-tolerated, potent, orally active 5α-reductase inhibitor in man.

Liquid chromatographic determination of total celiprolol or (S)-celiprolol and (R)-celiprolol simultaneously in human plasma

A method has been developed for the determination of total celiprolol (sum of enantiomers) or the enantiomers (R)-celiprolol and (S)-celiprolol in plasma by high-performance liquid chromatography with UV and fluorescence detection. After extraction from alkalinized plasma with methyl-tert.-butyl ether and back-extraction into 0.01 M HCl (for total celiprolol determination) or after evaporation of the organic phase and derivatisation with R(-)-1-(1-naphthyl)ethyl isocyanate (enantiomer determination), total celiprolol or its diastereomeric derivatives were chromatographed on a reversed-phase HPLC column with a mixture of acetonitrile and phosphate buffer pH 3.5 (+0.05% triethylamine). Acebutolol was used as internal standard. Linearity was obtained in the range of 5 to 2000 ng/ml for total and 2.5 to 500 ng/ml for enantiomer determination. Intra-day and inter-day variation was lower than 10%. The method can be applied for analysis of plasma samples obtained from patients treated with oral racemic celiprolol doses.

Moexipril does not alter the pharmacokinetics or pharmacodynamics of warfarin.

SummaryThe potential effect of moexipril, a new converting enzyme inhibitor, on the pharmacokinetics and pharmacodynamics of a single dose of warfarin has been investigated.Ten healthy male volunteers received in a randomised crossover fashion a single oral dose of 50 mg warfarin sodium alone and together with the first dose of 6 days of oral treatment with moexipril 15 mg o.d.Mean oral plasma clearance of (R)-warfarin was 175 ml·h−1 in the absence and 181 ml·h−1 in the presence of moexipril, and the corresponding values for (S)-warfarin were 248 ml·h−1 and 249 ml·h−1. Apparent volume of distribution, peak plasma concentration, time to reach peak concentration and area under the plasma concentration-time curve both of (R)- and (S)-warfarin were not significantly affected. Moexipril did not alter the maximum prothrombin time (20.3 versus 20.1 s, respectively in the absence and presence of moexipril), time to maximum response (48.0 versus 50 h) and area under the prothrombin time versus time curve.The results suggest that a clinically important interaction between moexipril and warfarin is unlikely to occur in patients treated with both drugs.

Comparative systemic availability of rectal and oral preparations of microcrystalline theophylline

SummaryA study was carried out in 5 healthy male volunteers of three experimentally developed rectal suppositories of microcrystalline theophylline and aminophylline, containing equivalent doses of 375 mg theophylline, to assess their ability to provide rapid and substantial plasma levels of theophylline. Rapidly-dissolving theophylline oral tablets and theophylline solution (‘Theolair”) were used as the standard formulations. Plasma theophylline concentrations were measured using an HPLC-assay method. One rectal suppository, the B-PEG formulation was found to be bioequivalent to the highly available oral tablets QTheolair”). Absorption was rapid and the plasma concentration profile of theophylline was essentially similar over the 24-hour period following the test doses. Both routes of administration were well tolerated without occurrence of any side-effects.

Diflunisal versus aspirin: a comparative study of their effect on faecal blood loss, in the presence and absence of alcohol

Faecal blood loss was measured in normal male volunteers using 51Cr-labelled red cells. In a double-blind parallel study in 10 subjects, the effect of 250 mg diflunisal twice daily was compared with 750 mg aspirin 4-times daily. Drugs were taken during two 7-day periods separated by a 1-week control period. Mean daily faecal blood loss during the two treatment periods was 0.32 ml and 0.53 ml in the diflunisal group versus 6.87 ml and 3.20 ml in the aspirin group. Diflunisal did not significantly increase blood loss, while aspirin had a significant effect. In a double-blind crossover study in 12 subjects, the effect of 250 mg diflunisal twice daily was compared with 600 mg aspirin 4-times daily. Alcohol (120 ml, 40%) was added during the last 2 days of each 6-day treatment period. Faecal blood loss was not significantly affected by diflunisal and there was also no significant effect on blood loss when alcohol was co-administered. Aspirin significantly increased faecal blood loss and this effect was significantly enhanced by the addition of alcohol.