Metabolism of hydralazine in man. Part II: Investigation of features relevant to drug safety.

The metabolism of hydralazine (1-hydrazinophthalazine hydrochloride, Apresoline) was investigated in 17 hypertensive patients of known acetylator status who were chronically treated with oral doses of 50 mg b.i.d. or 100 mg b.i.d. hydralazine. The acetylator status was assessed either by the monoacetyldapsone/dapsone ratio or by the isoniazide plasma half-life. In each patient the tests were performed on two different days of treatment and they included the analyses of four hydralazine metabolites (NAc-HPZ, 3OH-MTP, MTP and TP), as well as apparent hydrazine in urine and also the determination of plasma concentrations of apparent hydralazine. All data of the two experiments performed within an interval of at least five days were in good agreement, thus indicating that the patients were in pharmacokinetic steady states. No correlation was detectable between any of the determined amounts of metabolites of hydralazine and the assigned acetylator status of the patients. On the other hand the rank order of the urinary yields of the two main metabolites NAc-HPZ and 3OH-MTP suggest to be a representative scale for the patients' status in respect to the biotransformation of the drug itself. The urinary yield of apparent hydrazine is dependent on the pH applied during the analyses and is not correlated with any of the other data recorded. The findings of the present study support the assumption that measuring a relevant prominent metabolite of the drug itself may lead to a more reliable assessment of the particular metabolic status of the patients than by classification through a non treatment related foreign compound.(ABSTRACT TRUNCATED AT 250 WORDS)

[The percutaneous absorption of diclofenac]. / Die perkutane Resorption von Diclofenac.

The percutaneous absorption of diclofenac diethylammonium 1.16% (w/w) in a combination of emulsion cream and gel (Voltaren Emulgel) and of diclofenac sodium 1% (w/w) in a cream formulation (Voltaren cream) was investigated in guinea-pig, rabbit and man. The percutaneous absorption of diclofenac sodium in guinea-pig was 3 to 6% of the dose when the cream formulation in doses of 320, 100 or 40 mg was applied on 10 cm2 of occluded skin and left in place for 6 h. The transdermal delivery of 14C-labelled diclofenac yielded plateau plasma concentrations of radiotracer from 1.5 h after application until removal of the residual cream. Subsequently the steady state drug depots in the skin and muscle tissue were depleted promptly. During daily administration the steady state levels in the muscle tissue in proximity to the application site were about 3 times higher than in distant muscle tissue. By topical application on knee joints of rabbits diclofenac penetrated into the patellar ligament, the adipose corpus and the synovial fluid. In man the percutaneous absorption was 6% of the dose when the Emulgel formulation was spread by 5 mg/cm2 and left for 12 h on non-occluded skin. The pattern of metabolites of diclofenac in human urine was the same after topical and oral administration. In man, upon daily topical administration of 3 times 2.5 g cream formulation (10 mg/cm2) the diclofenac steady state plasma levels were 20 to 40 nmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Theoretical aspects pertinent to the interpretation of concentration data.

Toxicological risk assessment requires knowledge of the kinetics of the test compound and its metabolites in the respective animal species. The toxic effects are dependent on the maximum, minimum, integral and mean systemic exposure as well as its fluctuation index at steady state. If these variables are set appropriately, defined toxicological hypotheses can be tested: the assessment of the no-effect dose level, the evaluation of the toxicological significance of high peak versus attenuated systemic exposure and the toxicological rating of species-specific metabolic pathways.

Estimation of the individual metabolic state and its consideration in optimal pharmacotherapy.

The efficacy and safety of long-term therapy depends on the dose regimen. The early recognition of individual pharmacokinetic defects is a professional task of the clinical pharmacologist. The application of test compounds has been used to differentiate between slow and fast metabolizers. Modern techniques for identifying and quantitating drug metabolites facilitate the determination of the individual metabolic state without resorting to compounds foreign to the particular therapy. This paper exemplifies this principle by examining the metabolism and pharmacokinetics of carbamazepine, oxprenolol, hydralazine, maprotiline and diclofenac sodium. The systematic collection and analysis of representative samples of data is shown to be a prerequisite for the conclusive assessment and interpretation of the individual metabolic state.

Epidural morphine for postoperative analgesia: a double-blind study.

Postoperative analgesia and the side effects of epidurally injected morphine were investigated in a double-blind study. Following lumbar epidural anesthesia for orthopedic operations, 174 patients received, in a randomized, double-blind fashion, either 0.1 mg/kg of morphine epidurally, 0.1 mg/kg of morphine intramuscularly, or saline epidurally at the end of surgery. Following epidural morphine, postoperative pain was les frequent, less intense and of shorter duration, use of analgesics and sedative was less frequent; and the postoperative feeling of well-being rated better than after systemic morphine or epidural saline. These effects were more frequent when bupivacaine was used for operative epidural anesthesia than when mepivacaine was used. The results were age independent. Side effects following epidural morphine included pruritus and disturbances of micturition. Nausea, vomiting, fatigue, and headache were of comparable frequency in the three groups.

Rapid, sensitive determination of unchanged promethazine in biological material using a nitrogen-selective flame ionization detector. Identification of metabolites by gas chromatography-mass spectrometry.

A rapid, sensitive method has been developed to study the kinetics of unchanged promethazine (PM) in biological material using a nitrogen-selective flame ionization detector (N-FID). Unchanged PM is distinguished from its desmethyl metabolite. Sample clean-up of several biological fluids (rat plasma, blood, urine, liver and kidney homogenates) was studied and gas chromatographic (GC) conditions optimized. Usually 50 microliters-1.0 ml samples are extracted into n-heptane by shaking with NaOH, re-extracted into H2SO4 and again extracted into n-heptane by addition of NaOH. Finally, the organic phase is separated, concentrated under N2 and PM determined by N-FID. However, a rapid, single-step method requiring only NaOH extraction into n-heptane may be used whenever GC background permits. Imipramine is used as an internal standard for calibration by peak height ratios in the overall range 5--1500 ng PM per sample. Recovery of both methods is high (97--99%) but precision of the single-step method is lower (relative S.D. 10% versus 3--4%). Use of sample volumes up to 1 ml allows accurate determination of concentrations as low as 10 ng/g. Examples of applications to commonly used animal models employing PM are given and simple adaptation for clinical samples suggested.

Two rapid methods for the simultaneous gas-liquid chromatographic determination of carbon tetrachloride and chloroform in biological material and expired air.

Two simple gas-liquid chromatographic techniques were developed for the simultaneous determination of CCl4 and CHCl3 in biological material and expired air and principally for use in the well-known CCl4-induced hepatotoxicity model: a non-extractive head-space analysis by flame ionization detection (FID) and a single-step toluene extraction using electron-capture detection (ECD). For head-space analysis, blood or liver homogenate is incubated with buffer in sealed reaction vials and the head-space vapour sampled for FID determination. Absolute signal response to CCl4 and CHCl3 was used for calibration in the range 5-500 microgram per gram of biological material. The method is reasonably accurate, e.g. CCl4 in liver homogenate 98 +/- 21.8 (S.D.) %, in blood 94 +/- 13.3%, but the precision is poor (rel. S.D. 10-20%). Air samples in volumes of up to 2 ml may be determined by direct FID injection. The ECD sensitivity of to CCl4 and CHCl3 permits determination of microsamples (50-500 microliters) of blood and liver homogenate by extraction with buffer into toluene containing an internal standard (propyl iodide). The linear range of the detector allowed calibration by peak area ratio in the concentration range (10-1500 ng of CCl4 or CHCl3 per millilitre of toluene. The accuracy of the method is high, e.g. in blood CHCl3 101 +/- 9.5 (S.D.)%, CCl4 100 +/- 15.2%, as is the precision: rel. S.D. ca 5% for both CCl4 and CHCl3. For elimination studies, CCl4 and CHCl3 in air may be trapped in toluene and determined by ECD. Recovery of known amounts of CCl4 and CHCl3 from air chamber was high: 100 +/- 4.7 (S.D.)% and 111 +/- 10.9%, respectively, and reduction of CCl4 to CHCl3 by the trapping system negligible (less than 0.01%). Cross-checking of the methods and application to the commonly used CCl4 hepatotoxicity model is demonstrated.

[The problem of hemoperfusion in poisonings: ineffectiveness in maprotiline poisoning]. / Zur Frage der Hämoperfusion bei Vergiftungen: Unwirksamkeit bei Maprotilin-Intoxikation.

A case of self-poisoning with maprotiline presenting with coma stage III was treated by resin hemoperfusion for 9 hours using an XAD-4 resin cartridge. Plasma levels of about 800 ng/ml maprotilin were initially found. After 5 hours of hemoperfusion progredient clinical improvement was noticed without decreasing tendency of the blood drug levels. The theoretical extraction efficiency calculated from the maprotiline blood levels and the perfusion rate yielded 50 mg for maprotiline and 16 mg for desmethylmaprotiline and was in good agreement with 60.5 mg of maprotiline and 17.3 mg of desmethylmaprotiline recovered from the resin cartridge at the end of the hemoperfusion. The in vitro binding capacity for maprotiline was estimated to be 230 mg per g of resin. These results demonstrate that XAD-4 resin efficiently binds maprotiline. However, because of the very low blood concentrations due to the large volume of distribution, whole body concentrations are minimally affected by resin hemoperfusion. Main complications consisted in thrombocytopenia extending over 24 hours after stopping hemoperfusion, anemia, a short initial decrease of blood pressure and an episode of premature ventricular beats.

The renal elimination of rifampicin as a function of the oral dose. A convenient way to assess relative bioavailability.

A spectrophotometric method for the quantitative determination of rifampicin in urine is described and its specificity and precision are discussed. It is shown that the mean cumulative urinary elimination of rifampicin is reproducible when the same dose is administered twice in two different experiments to the same group of volunteers. The percentage of the amount eliminated increases with increasing dose. The renal elimination of apparent rifampicin can be used as a parameter for assessment of relative bioavailability of rifampicin from oral dosage forms of the same nominal strength if an appropriate number of volunteers is involved in the test.