Pharmacokinetics and first clinical experiences with an antihypertensive dopamine (DA2) agonist.
The pharmacokinetic properties and first clinical experiences with the antihypertensive dopamine (DA2) agonist, carmoxirole, are summarized. In man carmoxirole was rapidly absorbed. On oral administration the maximum plasma concentration was reached after 2-3 h. The drug was metabolized, mainly to an ester-type glucuronide, and was excreted (unchanged carmoxirole plus glucuronide) largely by the kidneys. The plasma half-life of the parent compound was 5.5 h. For the dose range tested (0.5 to 1.5 mg) the pharmacokinetics were linear. The drug was rapidly distributed in animals but only very small amounts penetrated the blood-brain barrier. Carmoxirole did not affect supine blood pressure in healthy subjects, but under the conditions of the Schellong's test some orthostatic reactions occurred with high doses. In patients the blood pressure was reduced for at least 8 h after single oral doses. On repeated administration for several weeks a relevant antihypertensive effect was still measurable 12 and 24 h after dose. The most frequently reported adverse events have been headache, dizziness, tiredness, nausea, and gastric disorders. These symptoms are considered to be mainly due to blood pressure reduction, as is frequently observed at the beginning of antihypertensive therapy. In patients the incidence of orthostatic reactions is appreciably lower than in healthy subjects, and in both change of position was sufficient to relieve the symptoms.
Department of Clinical Research, E. Merck, Darmstadt, Germany.
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W
Meyer
K U
KU
Bühring
K
K
Steiner
W
W
Ungethüm
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E
Schnurr
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000818:Animals; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D015259:Dopamine Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy*; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000502:physiology; D014018:Tissue Distribution
D000959:Antihypertensive Agents; D015259:Dopamine Agents; D007211:Indoles; D011725:Pyridines; D017448:Receptors, Dopamine D2; C071485:carmoxirole