Pharmacokinetics, protein binding and metabolic profile of 3H-icometasone enbutate following intravenous, oral and intratracheal administrations to Sprague-Dawley rats.

Absorption, distribution and excretion of 3H-icometasone enbutate (9 alpha-chloro-11 beta,17 alpha,21-trihydroxy-16 alpha-methylpregna-1,4-diene-3,20-dione, 17-butyrate, 21-acetate, CAS 103466-73-5 CL09) were studied in male and female Sprague-Dawley rats after a single dose administration by intravenous (1 mg/kg), oral and intratracheal (2 mg/kg) routes. The metabolic profile after the different routes and protein binding were also determined. Independent of the route, the radioactivity was mainly excreted in faeces. Less than 10% of the dose were excreted in urine. The majority of the administered doses was recovered within 24 h postdose, and the total recovery of the doses administered was obtained. After oral and intravenous administration to bile-duct cannulated rats, most of the radioactivity was excreted in the bile (80% of the administered dose) and some radioactivity was found in the faeces. It can thus be concluded that some intestinal secretion occurred. After oral administration, mean maximum blood concentrations were obtained about 0.75 h postdose. For the intratracheal route, the radioactive dose administered was too low to determine precise blood pharmacokinetic parameters. However, the distribution study results allowed us to conclude that the drug was absorbed first from the lungs and then from the gastrointestinal tract. Immediately after the intravenous injection, the liver, the kidneys, the small intestine and its contents and the carcass presented the highest levels of radioactivity. 168 h postdose, low radioactivity was still measurable in these organs. In other tissues, the radioactivity decreased reaching the limit of quantification 72 h postdose. After oral administration, the maximum concentrations were observed 1 h after administration in the liver, the small intestine and its contents. Then the radioactivity decreased in most of the tissues but a slight increase at 72 and/or 120 h postdose was noted in large intestine contents, carcass, lungs, eyes. After intratracheal administration, the maximum radioactivity was observed in lungs and trachea. A few minutes later the radioactivity reached the gastrointestinal tract. The protein binding study showed a saturable binding in rat and human plasma without notable differences between the two species. The binding on human serum albumin was shown to be non saturable with a total binding capacity of 7.48 +/- 1.83 mumol/l, suggesting that other proteins were involved in CL09 binding. This binding was demonstrated to be reversible. CL09 was extensively metabolized since no unchanged CL09 was recovered in bile or urine and at least nine metabolites have been detected. The profiles seemed to be different according to the route of administration.

Pharmacokinetics of rimexolone after intra-articular administration.

The pharmacokinetics of rimexolone were investigated after intra-articular injection into the knee joints of patients with rheumatoid arthritis. After a single dose of 40 mg rimexolone the drug could be detected in plasma over 3 months. The suspension dissolves in the synovia very slowly and provides a sustained release of the steroid in the joint. Pharmacokinetic analysis was performed on the assumption that the disposition of rimexolone after intra-articular administration is absorption limited ("flip-flop-case"). Dose linearity was studied in a range from 40 to 200 mg. Total body clearance averaged 106 L/h and was independent of dose. The mean residence time of rimexolone in the knee joint is very long and averaged 25 days. It could be shown that the mean residence time of different glucocorticoids correlates well with the duration of their clinical effectiveness.

Reversible pharmacokinetic profiles of canrenoic acid and its biotransformed product. Canrenone in the rat.

Pharmacokinetic profiles of canrenoic acid (CRA) and canrenone (CR), the reversible metabolite of CRA, were studied in the rat after intraportal (pv) administration in comparison with those after intravenous (iv) administration using an interconversion model. In the clearances for the irreversible loss. CL20 of CR was larger than CL10 of CRA. Nevertheless, the real plasma clearance of CR was less than that of CRA. The distribution volume V1 of CRA was almost close to the real distribution volume Vss.real.D of CRA at the steady state. The hepatic available fraction of CRA, FH1 and sequential hepatic available fraction of generated metabolite, FH2, were estimated. Simultaneous computer multi-line fitting of plasma concentration-time data was carried out and the adequacy of pharmacokinetic parameters in this model was tested using the iterative nonlinear least-squares regression program, MULTI.

[Studies on the bioequivalence of canrenone using pharmacokinetic data and clinical effects]. / Untersuchungen zur Bioäquivalenz von Canrenon mittels pharmakokinetischer Daten und klinischem Effekt.

Canrenon, an active metabolite of spironolactone, and the combination of Canrenon with hydrochlorothiazide (HCT) were examined on patients with essential hypertension, cardial oedemas and oedemas of different origin, and than compared to a product available on the market. A correlation of the clinical effect (e.g. systolic blood pressure) with the morning steady state-data (blood values of Canrenon and HCT) has been achieved. The new preparations showed a good resorption in the gastro-intestinal tract. For an equivalent clinical effect, less Canrenon substance has been needed. A therapeutically satisfactory result has been reached with the administered dosage of both Canrenon and the comparison group. In the combination the higher dosage level should be chosen.