Circadian plasma level profile of lisuride in rats and mice after continuous administration via the diet.

Lisuride (Dopergin, CAS 18016-80-3), a dopamine D2 agonist, was administered to male and female rats and mice continuously via the diet for 14 days. The doses were 0.2 mg/kg/d in mice and 1 mg/kg/d in mice and rats. Plasma level profiles (0-22 or 24 h) were determined by measuring lisuride concentrations by radioimmunoassay. At all doses a plateau-like plasma level of lisuride was observed. A clear circadian rhythm of lisuride concentrations (highs during night, low levels during day) was found for male rats (1 mg/kg/d) and for male mice (0.2 mg/kg/d). Female animals did not show this phenomenon as pronounced. At the same dose of 1 mg/kg/d rats showed higher plasma levels than mice. For males the ratio of total AUCs was 1.9 and for female animals 8.6.

High-performance liquid chromatographic determination of terguride in solid dosage forms and plasma.

A simple and rapid HPLC method was developed to determine terguride in terguride hydrogenmaleate, coated tablets and plasma. The assay was carried out on a glass column of SGX CN (150 x 3.3 mm I.D.) using methanol and phosphate buffer solution (pH 7.0) as the mobile phase, with detection at 227 nm. Terguride was quantified using promethazine as an internal standard. The tablet matrix was extracted into methanol. Plasma samples were deproteinated with acetonitrile and the supernatant was injected into the HPLC system. The method is linear, quantitative and reproducible.

Quantitative determination of the dopamine agonist lisuride in plasma using high-performance liquid chromatography with fluorescence detection.

An HPLC method for the determination of lisuride hydrogen maleate in plasma is described. After addition of ergotamine tartrate as internal standard, plasma is extracted with diethyl ether. Following evaporation of the solvent and redissolving in methanol the extract is injected on a silica HPLC column and lisuride is monitored by fluorescence detection using an excitation wavelength of 322 nm and an emission wavelength of 405 nm. The method is sufficiently accurate and precise with a detection limit of 20 pg/ml lisuride in plasma. The usefulness of the method is demonstrated by measurements of lisuride levels after oral intake of a 0.6 mg dose of the drug by a healthy male volunteer, showing a peak level of 1266 pg/ml, 45 min after intake.

Kinetic analysis of central [76Br]bromolisuride binding to dopamine D2 receptors studied by PET.

The in vivo kinetic analysis of dopamine D2 receptors was obtained in baboon brain using positron emission tomography (PET) and [76Br]bromolisuride [( 76Br]BLIS) as radioligand. An injection of a trace amount of [76Br]BLIS was followed 3 h later by an injection of a mixture of [76Br]BLIS and BLIS in the same syringe (coinjection experiment). A third injection performed at 6 h was either an excess of unlabeled ligand (displacement experiment) or a second coinjection. This protocol allowed us to evaluate in the striatum of each animal and after a single experiment the quantity of available receptors (B'max) and the kinetic parameters including the association and dissociation rate constants (k + 1VR and k-1, respectively, where VR is the volume of reaction). The cerebellum data were fitted using a model without specific binding. All the parameters were estimated using nonlinear mathematical models of the ligand-receptor interactions including or not including nonspecific binding. The plasma time-concentration curve was used as an input function after correction for the metabolites. An estimate of standard errors was obtained for each PET study and for each identified parameter using the covariance matrix. The average values of B'max and KdVR were 73 +/- 11 pmol/ml tissue and 1.9 +/- 0.9 pmol/ml, respectively. The nonspecific binding was identifiable in the experiment where the last injection corresponded to a second coinjection. We found that approximately 6% of the striatal binding was nonspecific after a tracer injection of [76Br]BLIS. The nonspecific binding appeared to be reversible in the striatum but irreversible in the cerebellum.

The pharmacokinetics and pharmacodynamics of lisuride in healthy volunteers after intravenous, intramuscular, and subcutaneous injection.

The plasma concentration of lisuride and prolactin have been measured in twelve healthy male volunteers after IV, IM or SC injection of 25 micrograms lisuride hydrogen maleate as an aqueous solution. After IV administration the plasma lisuride fell in two phases with half-lives of 14 min and 1.5 h. Total clearance was 13 ml.min-1.kg-1. After IM and SC injection the plasma concentrations peaked at 12 to 15 min and the profiles were similar to that found after IV administration. The systemic availabilities were 90% and 94%, respectively. Prolactin concentrations were reduced by a maximum of 60% relative to the normal circadian rhythm after all three routes of administration. The treatments were well tolerated, the only adverse reactions reported by some of the volunteers being mild, transient dizziness, tiredness, and nausea.

Pharmacokinetics and endocrine effects of terguride in healthy subjects.

Plasma levels of the partial dopamine agonist, terguride, were measured by RIA in healthy volunteers after a single i.v. dose of 50 micrograms and on the first and seventh day of an oral treatment with 250 micrograms, 500 micrograms and 750 micrograms b.d. Basal and releasing hormone (TRH, GHRH, CRF, LHRH)-stimulated pituitary hormone secretion (PRL, TSH, GH, FSH, LH) and cortisol were also determined by RIA. Following the i.v. injection, plasma terguride levels declined biphasically, with half-lives of 0.2 and 1.5 h; total clearance was 17 ml.min-1.kg-1. The oral bioavailability of terguride over all doses was about 20%. Basal and TRH-stimulated prolactin levels were dose-dependently depressed, but the secretion of other hormones remained unaffected. Tolerance of terguride was excellent and there was no negative effect on performance or mood, nor on mixed-function oxygenase activity, assessed as urinary 6 beta-OH cortisol.

Pharmacokinetics and pharmacodynamics of terguride following intramuscular administration in cows and goats.

The pharmacokinetics of intramuscular terguride (transdihydrolisuride) was evaluated in a single-dose study in cows (doses 100, 62 and 31 micrograms/kg b.w.) and goats (dose 100 micrograms/kg b.w.). A radioreceptor assay was used to quantitative plasma terguride concentrations. The peak plasma concentrations of terguride were attained within 0.6 h of the drug administration and then decreased monoexponentially with half-life of 1.3 h (cows) and 2 h (goats). The pharmacokinetics of terguride in cows is nearly linear. Pharmacodynamics of terguride was expressed as reduction in plasma prolactin levels. Maximal decline in prolactin was observed 3-4 h following terguride administration and the effect lasted for about 24 h.

Pharmacokinetics of lisuride after subcutaneous infusion.

Six parkinsonian patients received a constant subcutaneous infusion of 60 micrograms lisuride per hour in the abdominal region for 2 hours. Plasma levels of the unchanged drug were measured by radio-immunoassay. During infusion, a steady state plasma level of 0.78 +/- 0.19 ng/ml was achieved. After discontinuation of the infusion, concentrations declined with a half-life of 1.4 +/- 0.4 hour. The total clearance of lisuride was 20 +/- 6 ml/min/kg. Due to the low interpatient variability of plasma levels, a good control of clinical effects is to be expected.

The pharmacokinetics and biotransformation of 14C-lisuride hydrogen maleate in rhesus monkey and in man.

14C-labelled lisuride hydrogen maleate was administered intravenously (25 micrograms) and orally (200 micrograms) to three male and three female elderly volunteers. Following i.v. injection radioimmunologically determined plasma levels of unchanged lisuride showed a three-phasic decline with half-lives of 3 minutes, 16 minutes and 2.9 hours. The total clearance was 16 +/- 9 ml/min/kg. Bioavailability was estimated to be 14% of oral dose. Determination of 14C-radioactivity did not show any specific enrichment of lisuride metabolites in cellular components of blood. The drug was almost totally metabolized and its degradation products were eliminated equally via the kidney and liver. Total recovery was about 90% of dose. The elimination half-life was 10 hours. Small parts of the dose administered were renally excreted with a half-life of 23 hours. Lisuride is metabolized extensively. HPLC radiochromatograms of freely extractable metabolites from urine did not show marked differences between both routes of administration. More than 15 compounds were freely extractable, only one of them represented more than 5% of dose. Phase II reactions were quantitatively unimportant. From rhesus monkey urine 6 metabolites were isolated. Chemical structures were proposed for 5 of them. They were assigned to the pattern of freely extractable human urinary metabolites and covered about 50% of radiolabel corresponding to about 13% of dose. The main freely extractable urinary metabolite was thought to be the 2-keto-3-hydroxy-lisuride derivative. Structures of the other four metabolites and earlier observations on the stability of the N'-ethyl-3H label led to the interpretation of independent changes of lisuride by different enzymatic processes such as oxidative N-deethylation, hydroxylation of the benzene system, monooxygenation at C2 and C9, and oxidation of double bonds at C2/C3 and C9/C10.

Radioreceptor assay for ergot derivatives, transdihydrolisuride and lisuride, in biological fluids.

The development of a sensitive radioreceptor assay (RRA) for transdihydrolisuride (TDHL) and lisuride, as well as the synthesis of tritiated TDHL, is described. The method is based upon the competition between 3H TDHL and TDHL or lisuride for rat brain dopaminergic receptors. Linear calibration graphs were obtained in the range of 0.2-9 pmol for an ergot derivative. Relative affinities of the main metabolites, deethylated and dideethylated on the urea part of the molecule are 3.6% and 1.5%, respectively, as compared to the parent drug. To verify the method, plasma levels of TDHL were determined in rats after oral administration.

Lisuride treatment in Parkinson's disease: clinical and pharmacokinetic studies.

Our study of 28 patients has shown lisuride to share a comparable profile of antiparkinsonian effects and adverse reactions to that found with bromocriptine. The similarity in clinical response to lisuride and bromocriptine in the same group of patients contrasts with the pharmacological differences that have been established between them in animal studies. There were considerable individual differences in the patients' preference of bromocriptine or lisuride. The daily intake requirements of each drug for optimal benefit also varied widely from one patient to another. The preliminary results of pharmacokinetic studies with lisuride suggest several explanations for the differences in daily dosage requirements. Although the mean optimal daily dose of lisuride was 4.5 mg, some patients required up to 10 mg. Eleven of the patients have continued on lisuride for more than 1 year. Our clinical impression is that problems with chronic levodopa therapy, such as dyskinesia and fluctuations in efficacy, are reduced in some patients taking either lisuride or bromocriptine.

Radioimmunoassay of plasma lisuride in man following intravenous and oral administration of lisuride hydrogen maleate: effect on plasma prolactin level.

The development of a sensitive radioimmunoassay for the determination of lisuride in plasma is described. The antiserum against lisuride-4-hemisuccinate-BSA was raised in rabbits. Using this method the plasma levels of lisuride were monitored following one intravenous (25 microgram) and two oral (100 microgram and 300 microgram) doses of lisuride hydrogen maleate in three female and three male volunteers (intra-individual comparison). The plasma prolactin was also determined by radioimmunoassay. Following i. v. injection, the concentration of lisuride declined in three phases, with half-lives of 5 min, 25 min and 2 h. The total plasma clearance of 800 +/- 250 ml X min-1 was in the range of "plasma flow" through the liver. In agreement with the high rate of biotransformation, the bioavailability of lisuride administered orally was 10% +/- 7% of the 100-microgram dose, and 22% +/- 7% of the 300-microgram dose. The plasma prolactin was lowered to 3%-18% of its pretreatment value depending on the route of administration and the dose. The reduction appeared to be short-lived and to be directly dependent on the plasma concentration of lisuride. Following intravenous injection, the prolactin level declined after a so far unexplained lag-time of 0.5 h.