Metabolic profiling of the Uncaria hook alkaloid geissoschizine methyl ether in rat and human liver microsomes using high-performance liquid chromatography with tandem mass spectrometry.

Geissoschizine methyl ether (GM) is an indole alkaloid found in Uncaria hook, which is a galenical constituent of yokukansan, a traditional Japanese medicine. GM has been identified as the active component responsible for anti-aggressive effects. In this study, the metabolic profiling of GM in rat and human liver microsomes was investigated. Thirteen metabolites of GM were elucidated and identified using a high-performance liquid chromatography with tandem mass spectrometry method, and their molecular structures were proposed on the basis of the characteristics of their precursor ions, product ions, and chromatographic retention times. There were no differences in the metabolites between the rat and human liver microsomes. Among the 13 identified metabolites, there were two demethylation metabolites, one dehydrogenation metabolite, three methylation metabolites, three oxidation metabolites, two water-adduct metabolites, one di-demethylation metabolite, and one water-adduct metabolite followed by oxidation. The metabolic pathways of GM were proposed on the basis of this study. This study will be helpful in understanding the metabolic routes of GM and related Uncaria hook alkaloids, and provide useful information on the pharmacokinetics and pharmacodynamics. This is the first report that describes the separation and identification of GM metabolites in rat and human liver microsomes.

Tranquilizers, analgetics and antidepressants in patients treated with hemodialysis.

Tranquilizers, analgetics and antidepressants are applied in different ranges in the treatment of patients on hemodialysis. Due to many different pharmacokinetic properties, no perfect rules for dosage in acute or chronic hemodialysis exist. Adequate applicable drugs without adaptation disregarding different states of renal failure are such with predominate hepatic metabolism and elimination or with inactive metabolites. In the management of acute renal failure, usually in connection with multiple organic disorders, a nonschematic, individually adapted therapy is indicated. In some substances, therapy can be determined by control of plasma concentration levels, in other drugs dosage is possible exclusively according to clinical effects. Substances with side effects on coagulation or acid-base equilibrium should be avoided. It is recommendable to get well acquainted with one substance out of each group in order to avoid polypragmasy.

Formation of nitroso compounds and mutagens from tranquilizers by drug/nitrite interaction.

The formation of nitroso compounds and mutagens by drug/nitrite interaction was screened for 14 tranquilizers. The drug (0.05 M) was reacted with nitrite (0.5 M) at pH 3-3.5. After 4 h at 37 degrees C, nitroso compound formation was observed for flupentixol, chlordiazepoxide, spiperone, thiothixene, and chlorprothixene in more than 40% yield. Mutagenicity was found in the reaction products of opipramol, chlordiazepoxide, bromazepam, thiothixene, and carpipramine by the Ames assay using Salmonella typhimurium TA98 and TA100 as tester strains.

Drug prescribing in hepatobiliary disease.

Liver disease in man is associated with a variety of pathophysiological processes which may influence the disposition of drugs in several ways. Interpretation of the observed pharmacokinetic changes in liver disease requires an understanding of the relationship between systemic drug clearance (Cls), volume of distribution (Vd) and the elimination half-life [t1/2(beta)], i.e. t1/2(beta) = 0.693 . Vd/Cls. Half-life will be a measure of the fluctuation in drug level one may expect with continued administration of a drug while clearance will determine the dose required to achieve a particular steady state level. Liver disease may affect clearance and volume of distribution and so produce changes in half-life; in addition, alterations in plasma binding of drugs may occur and so influence free (unbound) drug levels. It is also possible that the end organ response, particularly in the case of sedative drugs, may be affected by liver disease. Other factors such as age, nutrition, smoking, and concomitant drug therapy may also influence drug elimination in patients with liver disease. At the present time, caution should be exercised in prescribing drugs to patients with liver disease and the dose should be titrated to the clinical response. The development of liver 'function' tests using model or marker drugs may offer some help to the prescriber in the future and enable a less empirical approach.

[Use of gas chromatography--mass spectrometry system in toxicology]. / Aplikace systému plynové chromatografie - hmotové spektrometrie v toxikologii

In the presented paper experiences with the practical usage of gas chromatography - mass spectrometry system are given. Cases of the identification of forbidden doping drugs and some significant groups of medicaments are described. The possibility of the identification of drug metabolites and interfering substances is pointed as well. Examples of chemical ionization usage are given from literature papers. This work points out the advantages of both methods for the identification of drugs in biological material. The priority and possibility of both procedures are evaluated critically.