Disposition and chemical stability of telmisartan 1-O-acylglucuronide.

Telmisartan 1-O-acylglucuronide, the principal metabolite of telmisartan in humans, was characterized in terms of chemical stability and the structure of its isomerization products was elucidated. In addition, pharmacokinetics of telmisartan 1-O-acylglucuronide were assessed in rats after i.v. dosing. Similar to other acylglucuronides, telmisartan 1-O-acylglucuronide and diclofenac 1-O-acylglucuronide, which was used for comparison, showed the formation of different isomeric acylglucuronides on incubation in aqueous buffer. The isomeric acylglucuronides of telmisartan consisted of the 2-O-, 3-O-, and 4-O-acylglucuronides (alpha,beta-anomers). First order degradation half-lives of 26 and 0. 5 h were observed on incubation in buffer of pH 7.4 for the 1-O-acylglucuronides of telmisartan and diclofenac, respectively. This indicated that the 1-O-acylglucuronide of telmisartan was among the most stable acylglucuronides reported to date. The high stability of telmisartan 1-O-acylglucuronide was confirmed by in vitro experiments that indicated only very low covalent binding of telmisartan acylglucuronide to human serum albumin but a considerable amount of covalently bound radioactivity with the acylglucuronide of diclofenac. After i.v. dosing to rats, telmisartan 1-O-acylglucuronide was rapidly cleared from plasma with a clearance of 180 ml/min/kg, compared with 15.6 ml/min/kg for the parent compound. Because telmisartan 1-O-acylglucuronide exhibited a comparably high chemical stability together with a high clearance that resulted in low systemic exposure, the amount of covalent binding to proteins should be negligible compared with other frequently used drugs, such as furosemide, ibuprofen, or salicylic acid.

Activation of human cytochrome P-450 3A4-catalyzed meloxicam 5'-methylhydroxylation by quinidine and hydroquinidine in vitro.

In humans, meloxicam is metabolized mainly by cytochrome P-450 (CYP)-dependent hydroxylation of the 5'-methyl group. The predominant P-450 enzyme involved in meloxicam metabolism is CYP 2C9, with a minor contribution of CYP 3A4. Quinidine, a CYP 3A4 substrate commonly used as a selective in vitro inhibitor of CYP 2D6, was found to markedly increase the rate of meloxicam hydroxylation during in vitro experiments with human liver microsomes. A similar activation was observed with other compounds that are structurally related to quinidine. Besides quinidine, quinine and hydroquinidine were the most potent activators of meloxicam hydroxylation. Using expressed cytochrome P-450 enzymes and selective chemical inhibitors of CYP 2C9 and CYP 3A4, it was found that quinidine markedly increased the rate of CYP 3A4-mediated meloxicam hydroxylation but was virtually without effect on CYP 2C9. Kinetic analysis was performed to obtain insight into the possible mechanism of activation of CYP 3A4 and into the mutual interaction of quinidine/hydroquinidine and meloxicam. Quinidine and hydroquinidine decreased Km and increased Vmax of meloxicam hydroxylation, which was consistent with a mixed-type nonessential activation. Meloxicam, in turn, decreased both Km and Vmax of quinidine metabolism by CYP 3A4, indicating an uncompetitive inhibition mechanism. These results support the assumption that CYP 3A4 possesses at least two different substrate-binding sites. A clinically relevant effect on meloxicam drug therapy is not expected, because the most likely outcome in practice is moderately decreased meloxicam plasma concentrations.

Quantitation of the new hypoglycaemic agent AG-EE 388 ZW in human plasma by automated high-performance liquid chromatography with electrochemical detection.

A sensitive and selective high-performance liquid chromatographic assay has been developed for a new hypoglycaemic agent AG-EE 388 ZW (I) in human plasma. Plasma samples containing I were acidified with 0.2 M hydrochloric acid, directly injected into C2 reversed-phase pre-columns, and cleaned up on-line. After pre-column switching, the substance was separated isocratically in 15 min on a C18 reversed-phase column. Quantitation was performed after amperometric detection by external standard calibration curves. The linearity of the assay was demonstrated over the therapeutic concentration range 5-200 ng/ml. between-day coefficient of variation was 9.2% at 30 ng/ml. The limit of detection was 5 ng/ml in plasma. Determination of human plasma samples after intravenous and oral administration of 1 mg of 14C-labelled I demonstrated the applicability of the assay for pharmacokinetic studies in humans.

[Pharmacokinetics and laxative effect of bisacodyl following administration of various dosage forms]. / Pharmakokinetik und laxierende Wirkung von Bisacodyl nach Gabe verschiedener Zubereitungsformen.

Since its introduction into the market in 1952, bisacodyl has been successfully used worldwide as a laxative. In discussions on the kinetics and the laxative effect, it is often neglected that results obtained after the administration of the pure compound bisacodyl cannot be transferred to distinctive bisacodyl formulations. The aim of the present investigation is therefore to study the absorption and the plasma level profile and to correlate plasma level profile and laxative effect after the administration of various dosage forms. 12 healthy volunteers were administered with 10 mg bisacodyl as an experimental solution, with an acid resistant, commercially available Dulcolax Dragees (2 x 5 mg) and with a 10 mg Dulcolax suppository. Following glucuronidase cleavage, mean maximum plasma levels of 236.5 +/- 59.2 ng/ml of bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM) were reached after the administration of the solution 1.7 h post administration (p.a.), however, the laxative effect did not occur until 5.7 h +/- 0.7 h p.a. The dominant biological half-life of deconjugated BHPM, the diphenol of bisacodyl which circulated as BHPM-glucuronide, was about 16.5 +/- 4.2 h. The dragee yielded the desired low plasma levels which were between 7 and 47 ng/ml at 4-10 h p.a. In comparison to the solution only 16% were absorbed after the administration of the dragee. The laxative effect started 7.7 h +/- 1.7 h p.a. with no apparent relationship between effect and plasma level. The administration of the suppository resulted 20 +/- 10 min p.a. in a prompt laxative effect, although in 6 out 12 subjects, the plasma levels were below the detection limit.(ABSTRACT TRUNCATED AT 250 WORDS)

Fully-automated assay by liquid chromatography for routine drug monitoring in body fluids--method development with biological samples.

A fully-automated liquid chromatograph based on alternated pre-column enrichment technique has been developed for routine drug monitoring of body fluids using a column switching technique. Advantages of the method include the facility of direct injection of the body fluid onto the chromatograph and the simultaneous detection of both polar and non-polar metabolites under isocratic or gradient elution conditions.

Fully automated high-performance liquid chromatography. A new chromatograph for pharmacokinetic drug monitoring by direct injection of body fluids.

A new fully automated high-performance liquid chromatography is described which detects drugs from directly injected plasma (urine, saliva) without sample pretreatment. The apparatus consists of a programmable automatic sampling unit, which is connected via two alternating working pre-columns to an analytical column ("alternating pre-column sample enrichment"). The new device is able to operate with directly injected body fluids like an auto-analyzer and is especially useful for pharmacokinetic and clinical studies, where drug concentrations have to be determined from plasma, urine or saliva.

[Ambroxol, studies of biotransformation in man and determination in biological samples (author's transl)]. / Ambroxol, Untersuchungen zum Stoffwechsel beim Menschen und zum quantitativen Nachweis in biologischen Proben.

15 mg trans-4-[2-amino-3,5-dibromo-benzyl)-amino]-cyclohexanol-hydrochloride (ambroxol, NA 872) was administered i.v. and orally to healthy volunteers. The metabolic pattern in urine and plasma was similar for both routes of administration. Biotransformation reactions are straightforward, yielding two major products of phage I reactions identified as 6,8-dibromo-3-(trans-4-hydroxycyclohexyl)-1,2,3,4-tetrahydro-quinazoline and 3,5-dibromo-anthranilic acid. These metabolites as well as the parent compound are also converted to conjugates, predominantly glucuronides. Quantification of unlabelled ambroxol in biological fluids is achieved by radiochemical derivatisation with 14C-labelled formaldehyde in imitation of the biotransformation.

[The use of high-performance liquid chromatography in biochemical and medical analyses (author's transl)]. / Einsatz der Hochdruckflüssigkeitschromatographie (HPLC) in der biochemischen und medizinischen Analytik.

The HPLC (high-performance liquid chromatography) is applicable for all biochemical analyses, because of the wide variety of separation principles (adsorption-, partition-, ion-exchange- and steric exclusion-chromatography). Of exceptional importance is the reversed phase technique, a special case of partition chromatography. The sensitivity of detectors depends upon the structure of the respective substance, but is ordinarily lower -- apart from fluorescence detection -- than GLC-detectors. The development of new systems is going on. The HPLC is used in the quantitative determination of plasma levels of drugs and their metabolites. This is of special importance during the development of new drugs and for monitoring therapy. The measurement of concentrations of certain biogenic substances helps in diagnosis. An important field of application of HPLC is the use in sample clean-up for other analytical methods. In this application HPLC surpasses all other chromatographic techniques by fastness, reproducibility and suitability for automation.

Bis-(p-hydroxyphenyl)-pyridyl-2-methane: The common laxative principle of Bisacodyl and sodium picosulfate.

After both oral and rectal administration in humans (4,4'-diacetoxy-diphenyl)-(pyridyl-2)-methane (bisacodyl, Dulcolax) and 4,4'-(2-pyridyl-methylene)-diphenol-disulfuric acid semiester disodium (sodium picosulfate, Laxoberal) are hydrolyzed to bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM). In both cases BHPM is responsible for the laxative action. Experiments in rats and guinea pigs have shown that the hydrolysis of picosulfate, in contrast to that of bisacodyl, is attributable to the microorganisms of the intestinal flora.