Absorption and disposition including enterohepatic circulation of (14C) roquinimex after oral administration to healthy volunteers.

The absorption and disposition of roquinimex (Linomide) were studied in four male and two female healthy volunteers. The subjects received a single oral aqueous solution of 14C-labelled roquinimex, about 0.1 mg/kg, after an overnight fast. Blood samples were taken and urine and faeces were collected for 10 days after dosing. The plasma, urine and faeces concentrations of roquinimex and metabolites were determined by high-performance liquid chromatography (HPLC) with radiochemical detection. The metabolites were identified by HPLC-mass spectroscopy (MS). The plasma concentration-time profiles of roquinimex exhibited a rapid absorption followed by a bi-exponential disposition. A secondary peak was observed between 6 and 8 h, indicating enterohepatic circulation (EHC) of roquinimex. The terminal disposition half-life was estimated as 27 h. The primary metabolic pathways of roquinimex were hydroxylation, demethylation and conjugation. The major compound in plasma was roquinimex; metabolites were only occasionally detected. In urine and faeces, roquinimex accounted for 2% of the dose and conjugated and hydroxylated metabolites each accounted for about 30% of the dose. A model was derived for the plasma concentrations of roquinimex and the amount of urinary excreted roquinimex to take into account EHC. This model improved the goodness-of-fit according to common goodness-of-fit criteria. The values of the pharmacokinetic parameters were similar using compartmental and non-compartmental methods, indicating that the contribution of EHC of roquinimex is of minor importance in the evaluation of the pharmacokinetics of roquinimex.

Hepatic intra-arterial administration of doxorubicin and degradable starch microspheres. A pharmacokinetic study in the rat.

Urinary concentration of doxorubicin and its active metabolite doxorubicinol was followed in two groups of rats after hepatic intra-arterial injection of a single dose of 6 mg/kg doxorubicin or the same dose combined with 30 mg/kg Spherex (DSM). Urinary samples were collected during five days following administration. The concomitant DSM administration caused a significant decrease of the cumulative urinary excretion of intact doxorubicin; average five days of cumulative values were 73 and 103 micrograms respectively in the group with and without DSM. This indicates a DSM-induced reduction in systemic drug exposure. The elimination rates of doxorubicin or its active metabolite were not influenced by DSM. The decrease in excretion of the parent drug was not due to an interaction between the drug and DSM as evident by examining the binding of doxorubicin to DSM in vitro. Instead regionally altered drug distribution seems a plausible explanation to the reduction.

Metabolism of a novel nitrosourea, tauromustine, in the rat.

A novel nitrosourea, 1-(2-chloroethyl)-3-[2-(dimethylaminosulphonyl)ethyl]1-nitrosourea , tauromustine (TCNU), has been investigated for in vitro metabolism by different rat organs. Two kinds of reactions were seen, demethylation and denitrosation, both reactions required NADPH. These reactions were achieved by the liver microsomes and to a much lesser extent by lung microsomes. Induction of cytochrome P450 system with phenobarbital resulted in increased demethylation (10 times) and denitrosation (6 times) of tauromustine while induction with 3-methylcholanthrene did not have any significant effect on these reactions. Known inhibitors of different cytochrome P450 activities inhibited the demethylation and denitrosation of tauromustine to different levels. After oral administration of [14C]tauromustine a metabolic pattern similar to that observed in vitro experiments, was seen in the urine. The demethylated compound, which has alkylating cytotoxic activity, could be detected in the urine up to 8 hr after oral administration.

Plasma concentrations of estradiol and testosterone in single-drug polyestradiol phosphate therapy for prostatic cancer.

To evaluate the appropriate dosage of polyestradiol phosphate (PEP, Estradurin) as single-drug therapy, patients with metastatic prostatic carcinoma were given 80, 160 or 240 mg PEP every 4 weeks for at least 6 months. Injection of PEP was followed by rising plasma concentrations of estradiol in the first 2 weeks and slight fall in the next 2 weeks. Testosterone levels fell rapidly in the first 7 days and rose slightly in the following 3 weeks. Steady-state levels were reached after 2 months at the two lowest doses and after 4 months at the highest dose. Steady-state estradiol values increased in linear proportion to the dose. The steady-state concentrations of testosterone were about 45, 25 and 15% of the pretreatment values in the respective groups. At least 160 mg PEP at 4-week intervals is appropriate when the drug is used alone.

Differences in action of LH and FSH on the formation of cyclic AMP in the prepubertal rat ovary.

The actions of LH (NIH-LH-B8) and FSH (NIH-FSH-S9) on the cyclic AMP (cAMP) system in ovaries of 23-24 day old rats have been analyzed. An intravenous injection of LH increased ovarian cAMP levels in vivo after only 20 seconds. Maximal cAMP levels were seen after 15 min. Addition of LH or FSH in vitro to the isolated ovaries produced dose dependent increases of cAMP in the tissue as well as in the incubation medium. Low concentrations of LH caused a release of cAMP into the incubation medium without any detectable change in the tissue levels. The levels of cAMP in the incubation media for all concentrations of FSH were lower than the tissue levels, whereas for LH the opposite was found. In time-course experiments where the concentrations of LH (10 mug/ml) and FSH (100 mug/ml) were chosen to give similar tissue levels of cAMP, the release of the cyclic nucleotide into the incubation medium was approximately 2-3 times greater for LH than for FSH at the time periods studied (5-240 min). When LH and FSH were tested together in high concentrations, their effects were additive. When the ovaries were first incubated with FSH for 120 min followed by an incubation with LH, the stimulatory effect of LH was considerably reduced. When the order of the incubations was reversed, however, LH did not change the response to FSH. The results show that both LH and FSH have intrinsic effects on the cAMP system in the prepubertal rat ovary, but that the effects of the two gonadotrophins are not identical.