A review of the receptor-binding and pharmacokinetic properties of dopamine agonists.
BACKGROUND
Dopamine agonists (DAs), which can be categorized as ergot derived and non-ergot derived, are used in the treatment of Parkinson's disease.


OBJECTIVE
This review describes the pharmacologic and pharmacokinetic properties of selected DAs and relates these characteristics to clinical outcomes, with an emphasis on adverse events.


METHODS
Relevant articles were identified through a search of MEDLINE (to May 2006) using the terms dopamine agonists (or each individual drug name) and pbarmacokinetics, metabolism, drug-drug interaction, interactions, CYP450, fibrosis, valvular heart disease, tremor, clinical trials, reviews, and meta-analyses. Abstracts from recent sessions of the International Congress of Parkinson's Disease and Movement Disorders were also examined. Clinical studies with <20 patients overall or <10 patients per treatment group in the final analysis were excluded. All DAs that were graded at least possibly useful with respect to at least 3 of 4 items connected to the treatment/prevention of motor symptoms/complications in the most recent evidence-based medical review update were included. This resulted in a focus on the ergot-derived DAs bromocriptine, cabergoline, and pergolide, and the non-ergot-derived DAs pramipexole and ropinirole.


RESULTS
Bromocriptine, cabergoline, pergolide, and ropinirole, but not pramipexole, have the potential for drug-drug interactions mediated by the cytochrome P450 (CYP) enzyme system. The occurrence of dyskinesia may be linked to stimulation of the dopamine D(1) receptor, for which cabergoline and pergolide have a similar and relatively high affinity; bromocriptine, pramipexole, and ropinirole have been associated with a lower risk of dyskinesias. The valvular heart disease (VHD) and pulmonary and retroperitoneal fibrosis seen with long-term use appear to represent a class effect of the ergot-derived DAs that may be related to stimulation of serotonin 5-HT(2B) (and possibly 5-HT(2A)) receptors. The incidence of valvular regurgitation was 31% to 47% with ergot-derived DAs, 10% with non-ergot-derived DAs, and 13% with controls.


CONCLUSIONS
As reflected in the results of the clinical trials included in this review, dyskinesia associated with DA therapy may be linked to stimulation of the D(1) receptor. Fibrosis (including VHD) seemed to be a class effect of the ergot-derived DAs. Each of the DAs except pramipexole has the potential to interact with other drugs via the CYP enzyme system.
Kvernmo
Trond
T
Boehringer Ingelheim Norway KS, Asker, Norway. Electronic address: tkvernmo@osl.boehringer-ingelheim.com.
Härtter
Sebastian
S
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
Burger
Erich
E
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
D000818:Animals; D001971:Bromocriptine / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D000077465:Cabergoline; D018491:Dopamine Agonists / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000209:etiology; D004873:Ergolines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D006349:Heart Valve Diseases / Q000139:chemically induced; D006801:Humans; D007211:Indoles / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D010479:Pergolide / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000139:chemically induced; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*
D018491:Dopamine Agonists; D004873:Ergolines; D007211:Indoles; D011954:Receptors, Dopamine; C046649:ropinirole; D010479:Pergolide; D001971:Bromocriptine; D000077465:Cabergoline