Disposition of ropinirole in animals and man.

1. The disposition and metabolic fate of ropinirole, a novel compound indicated for the symptomatic treatment of Parkinson's disease, was studied in the mouse, rat, cynomolgus monkey and man, following oral and intravenous administration of ropinirole hydrochloride. 2. In all species, nearly all of the p.o. administered dose (94%) was rapidly absorbed from the gastrointestinal tract following administration of 14C-ropinirole hydrochloride. In rat and monkey, the compound distributed rapidly beyond total body water and was shown to cross the blood-brain barrier. Blood clearance of the compound was high, approximately equal to one-half the hepatic blood flow in the monkey and similar to the hepatic blood flow in rat. Terminal phase elimination half-lives for the compound were relatively short (0.5 and 1.3 h in rat and monkey respectively), although there was evidence of a second elimination phase in the monkey with an elimination half-life of approximately 5-11 h. Plasma concentrations of ropinirole after the intravenous dose were not determined in the mouse and were below the lower limit of quantification in man (0.08 ng/ml) at the doses used in the studies described in this paper. 3. In both animals and man, ropinirole was extensively metabolized. In the rat, the major metabolic pathway was via hydroxylation of the aromatic ring to form 7-hydroxy ropinirole. In mouse, monkey and man, the major pathway was via N-depropylation. The N-despropyl metabolite was metabolized further to form 7-hydroxy and carboxylic acid derivatives. Metabolites formed in all species were generally metabolized further by glucuronidation. 7-Hydroxy ropinirole is the only metabolite of ropinirole previously shown to possess significant dopamine agonist activity in vivo. In all species, the major route of excretion of ropinirole-related material after oral or intravenous administration of the compound was renal (60-90% of dose).

Tolerance to peripheral, but not central, effects of ropinirole, a selective dopamine D2-like receptor agonist.

Studies were conducted to determine possible development, and underlying mechanisms, of tolerance to the hypotensive effects of ropinirole (4-[2-(dipropylamino)ethyl]-1-3-dihydro-2H-indol-2-one HCl), a selective dopamine receptor agonist, following twice daily oral administration to cynomolgus monkeys and spontaneously hypertensive rats (SHR). Tolerance to the hypotensive effects of the compound developed in both species within one week of repeated dosing. Tolerance which developed in rats was dose-related and could not be attributed to altered plasma/drug concentrations or be overcome by increasing the i.v. challenge dose of ropinirole. Cross-tolerance was shown to the dopamine receptor agonist bromocriptine. Similar hypotensive responses to bethanidine were seen in rats treated with ropinirole or vehicle. Tolerance to hypolocomotor effects of the compound were not apparent in the same time frame. The dopamine D2 receptor antagonist, domperidone, caused hypertension in ropinirole-but not vehicle-treated rats. Results reported in this paper are not consistent with a down-regulation of peripheral dopamine D2-like receptors but suggest a compensatory increase in basal sympathetic tone.

Interactions between domperidone and ropinirole, a novel dopamine D2-receptor agonist.

1. Ropinirole, SK&F 101468 has been characterized preclinically as a specific dopamine D2-receptor agonist. Nine male healthy subjects were investigated for the effects on supine and erect heart rate and blood pressure, catecholamines and prolactin, of a single dose of 800 micrograms ropinirole preceded by a single dose of 20 mg domperidone or domperidone-placebo, and those of a single dose of domperidone followed by ropinirole-placebo. 2. Single doses of 800 micrograms ropinirole did not cause clinically significant changes in supine resting heart rate and blood pressure. However, they caused postural faintness on 3 min immobile upright standing on 10/26 occasions. 3. Pretreatment with 20 mg domperidone 1 h before administration of ropinirole prevented the postural symptoms in all but one subject. It did not alter ropinirole's plasma pharmacokinetics. 4. Ropinirole did not alter supine or standing catecholamine concentrations. 5. Domperidone increased the plasma concentrations of prolactin whereas ropinirole administered alone reduced them. A single dose of 800 micrograms ropinirole did not attenuate the prolactin increase induced by a single dose of 20 mg domperidone administered 1 h earlier.

Nephrotoxicity of Penicillium aurantiogriseum, a possible factor in the aetiology of Balkan endemic nephropathy.

Water-soluble components of a nephrotoxic isolate of Penicillium aurantiogriseum have been fractionated by sequential ion-exchange, size-exclusion gel filtration, reverse-phase silica chromatography and HPLC. Nephrotoxicity in the rat was confined to a size-exclusion fraction approximating to 1,500 daltons, which also inhibited DNA synthesis in cultured kidney cells. The more sensitive in vitro assay allowed toxicity to be followed to a sub-fraction from gradient-elution HPLC which in further HPLC resolved into a small group of glycopeptides. Recent Yugoslavian P. aurantiogriseum isolates, from a village in which the idiopathic human disease Balkan Nephropathy is hyperendemic, elicited a similar nephropathology and were acutely cytotoxic, reinforcing a need to regard this novel Penicillium nephrotoxin as a potential factor in human nephropathy.