Whole body quantitative autoradiographic study of the biodistribution of iobitridol in rats.

RATIONALE AND OBJECTIVES: Iobitridol is a new nonionic low-osmolality contrast medium. During preclinical development of this agent, it was of interest to verify that it behaves like other urographic and angiographic contrast agents (i.e., as a tracer of extracellular fluid). METHODS: Male and female rats were imaged using a quantitative autoradiographic method after intravenous administration of iodine-125-labeled product at a dose of 300 mg iodine/kg. RESULTS: The radioactivity was rapidly distributed with substantial uptake in the thyroid, kidneys, and skin after 10 minutes. The central nervous system showed no uptake. The radioactivity was rapidly eliminated (i.e., after 24 and 48 hours, only traces were found) except in the thyroid (because of free radiolabeled iodides present in small quantities in the administered solution). The considerable renal uptake after administration can be attributed to urinary excretion of the radioactivity (86% of the administered dose after 24 hours). Total elimination was achieved after 48 hours. No sex-related effects were observed. CONCLUSION: The absence of a target organ, the abundant and rapid urinary elimination, and the absence of transfer across the blood-brain barrier suggest that iobitridol is a tracer of extracellular fluid.

Routine determination of morphine, morphine 3-beta-D-glucuronide and morphine 6-beta-D-glucuronide in human serum by liquid chromatography coupled to electrospray mass spectrometry.

A robust liquid chromatographic mass spectrometric method capable of quantifying morphine, morphine 3-beta-D-glucuronide and morphine 6-beta-D-glucuronide down to 1.0 ng/ml, 5.0 ng/ml and 2.0 ng/ml respectively in human serum is presented. The method was validated over linear ranges of 1.0 to 20.0 ng/ml for morphine, 5.0 to 500.0 ng/ml for morphine 3-beta-D-glucuronide and 2.0 to 100.0 ng/ml for morphine 6-beta-D-glucuronide using deuterated morphine as internal standard. In tandem mass spectrometry conditions, the product ions of morphine-3-glucuronide and morphine-6-glucuronide were the ion m/z corresponding to the morphine moiety. By contrast morphine which presented numerous product ions after collision did not allowed a tandem methodology. Compounds were extracted on 100 mg C18 columns and analysed on the PE Sciex API 300 system equipped with a C18 column and electrospray ionisation interface. The interrun precision of quality controls (1.0, 2.0, 10.0, 20.0 ng/ml for morphine, 5.0, 10.0, 250.0, 500.0 ng/ml for morphine 3-beta-D-glucuronide and 2.0, 4.0, 50.0, 100.0 ng/ml for morphine 6-beta-D-glucuronide) was < or =9.3% and accuracy was between 97.9 and 109.8% for each analyte. Sample stabilities in biological matrix were also investigated. This method has been applied to pharmacokinetic analysis of morphine, morphine 3-beta-D-glucuronide and morphine 6-beta-D-glucuronide in human serum.

Pharmacokinetics of moxisylyte in healthy volunteers after intravenous and oral administration.

The concentration-time profiles of metabolites of moxisylyte, an alpha-blocking agent, in the plasma and urine of 12 healthy volunteers were investigated after intravenous (iv) and oral (two formulations) administration. The study was conducted with an open, randomized Latin squares design. Plasma and urine levels of moxisylyte and its biotransformation products were assayed by a specific HPLC method with fluorescence detection. Plasma levels declined in a monophasic or biphasic pattern depending on the subject. Two metabolites, conjugated desacetylmoxisylyte (DAM) and conjugated monodesmethylated DAM (MDAM), were found in plasma and urine. Unconjugated DAM was found in plasma only after iv administration. The apparent elimination half-lives of unconjugated DAM, conjugated DAM, and MDAM were 0.86, 1.7, and 3 h, respectively. The total amounts of metabolites (expressed as the equivalent of DAM) excreted in the urine were 75% after i.v. administration and 68 and 69% after oral administration of the two formulations. Oral absorption appeared to be complete for the two treatments. There was no statistical difference between the two oral formulations studied.

Skin distribution of fipronil by microautoradiography following topical administration to the beagle dog.

To investigate the localisation of fipronil in dog skin, [14C]-fipronil was topically applied to a male beagle dog (spot-on administration) at the therapeutic dose of 10 mg/kg. By means of autohistoradiography, the radioactivity was precisely detected in the skin and appendages at various intervals after application. Radioactivity was predominantly observed within the stratum corneum, the viable epidermis, and in the pilo-sebaceous units (mainly in the sebaceous glands and epithelial layers). [14C]-fipronil was significantly detected in these structures up to 56 days post-treatment, in the application zone (neck) but also in the lumbar zone, thus indicating the mechanical displacement of fipronil. No radioactivity was detected in either the dermal or the hypodermal layers, confirming the low percutaneous passage of fipronil.

Validation of liquid chromatographic and gas chromatographic methods. Applications to pharmacokinetics.

Validations of analytical methods are important for the generation of data for bioavailability, bioequivalence and pharmacokinetic studies. It is essential to use well defined and fully validated analytical methods to obtain reliable results that can be satisfactorily interpreted. This manuscript is intended to provide guiding principles for the evaluation of a method's overall performance. For this purpose, all of the variables of the method are considered, including sampling procedure, sample preparation, chromatographic separation, detection and data evaluation. The criteria considered are as follows: stability, selectivity, limits of quantification and of detection, accuracy, precision, linearity, recovery and ruggedness. Models used for analytical calibration curves are explained in term of validity and limitations, along with a presentation of the most common statistical considerations used to validate the model. Appropriate means of testing precision and accuracy, the most important factors in assessing method quality, are presented. Other issues, such as re-validation, cross-validation, partial sample volume, endogenous drugs and biological matrix of limited availability, are also discussed.

Effect of oral antacid administration on the pharmacokinetics of oral fluconazole.

Absorption and elimination of fluconazole after oral administration of a 100-mg capsule were unaffected by concomitant administration of an antacid containing aluminum and magnesium hydroxides.

Metabolism of 14C-thymoxamine in rat and man.

1. After oral administration of 14C-thymoxamine to rat and man the total 14C excreted in urine and faeces was determined. 2. Six metabolites were isolated from the excret of man and rat by chemical extraction and identified by g.l.c.-mass spectral analyses. 3. Two other metabolites, highly polar and resistant to enzymic hydrolysis, were isolated by extraction on XAD2 resin and h.p.l.c. analysis. These two metabolites were identified by n.m.r. and by mass spectrometry in the fast atomic bombardment mode. 4. These two major metabolites of thymoxamine in man and rat have been identified and characterized as the sulphate conjugates of desacetyl-thymoxamine and N-monodesmethyl-desacetyl-thymoxamine.