ROPINIROLE
BROMOCRIPTINE
PRAMIPEXOLE
ROTIGOTINE
APOMORPHINE
- Cytochrome P450 enzyme substrate: CYP1A2
- Action to be taken: Caution, Potential dose adjustment
- Rationale: Ropinirole is extensively metabolized by the liver. The major metabolic pathways are N despropylation and hydroxylation to form the inactive metabolites. In vitro studies show that CYP1A2 is also involved in the metabolism of ropinirole. There is thus the potential for inducers or inhibitors of this enzyme to alter the clearance of ropinirole. In vivo studies showed that smoked marijuana increased the clearance of theophylline and chlorpromazine by 50%. Exposure and systemic effects of CYP1A2 substrates may be decreased in individuals who smoke marijuana. Furthermore study with synthetic cannabinoids showed that synthetic cannabis may be a weak inhibitor of CYP1A2. Data shows that Cimetidine a weak inhibitor of CYP1A2 may potentially lead to increased concentrations of ropinerole. However the connection of these effects was not found in in vitro or in vivo studies of oral formulations of marijuana. Therefore, caution should be used during treatment with REQUIP, and adjustment of the dose of ropinerole may be required.
BROMOCRIPTINE
- Cytochrome P450 enzyme substrate: CYP3A4
- Action to be taken: Caution, Potential dose adjustment
- Rationale: In vitro studies showed that bromocriptine's main metabolic pathway involves CYP3A enzymes. Inhibitors and/or potent substrates for CYP3A4 might therefore inhibit the clearance of bromocriptine and lead to increased levels. The participation of other major CYP enzymes such as 2D6, 2C8, and 2C19 in the metabolism of bromocriptine has not been evaluated. Bromocriptine is also an inhibitor of CYP3A4. Given the low therapeutic concentrations of bromocriptine in patients, a significant interaction with drugs whose clearance is mediated by CYP3A4 should not be expected. In vitro evidence suggests that cannabis can inhibit the activity of CYP3A4 and thus increase serum concentration of drugs metabolized by that enzyme. In vivo study showed that the use of erythromycin (moderate CYP3A4 inhibitor) has significant effects on pharmacokinetics of bromocriptine. The data showed that during of concomitant administration with erythromycin, bromcoriptione's area under the concentration-time curve increased by 268%, and the peak plasma concentration (Cmax) increased to 4.6 times the Cmax from bromocriptine alone. Based on available data co-adminstration of marijuana with bromocriptine can lead to increased therapeutic or adverse effects of bromocriptine.
PRAMIPEXOLE
- Cytochrome P450 enzyme substrate: CYP2D6
- Action to be taken: No action needed
- Rationale: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4. Inhibition of CYP2D6 was observed with concentrations above therapeutic dose, indicating that pramipexole will not inhibit CYP enzymes in clinical setting. Furthermore cannabis showed little to no measurable inhibition of CYP2D6 indicating that the interaction with pramipexole is unlikely.
ROTIGOTINE
- Cytochrome P450 enzyme substrate: CYP2D6
- Action to be taken: No action needed
- Rationale In vitro studies indicate that multiple CYP-isoforms are capable of catalyzing the metabolism of rotigotine. If an individual CYP isoform is inhibited, other isoforms can catalyze rotigotine metabolism. Rotigotine, and its metabolites were analyzed in vitro for interactions with the human CYP 450 isoenzymes . Based on the results, no risk for inhibition of CYP1A2, CYP2C9 and CYP3A4 catalyzed metabolism of other drugs is predicted at therapeutic rotigotine concentrations. There is a low risk of inhibition of CYP2C19 and CYP2D6 metabolism of other drugs. In vitro evidence suggests that cannabis can inhibit the activity of CYP3A4 and CYP2C and thus increase serum concentration of drugs metabolized by these enzymes. Furthermore study with synthetic cannabinoids showed that synthetic cannabis may be a weak inhibitor of CYP1A2.Co-administration of rotigotine with cimetidine, an inhibitor of CYP1A2, CYP2C19, CYP2D6, and CYP3A4, did not alter the steady-state pharmacokinetics of rotigotine in healthy subjects. Therefore an interaction between rotigotine and marijuana is unlikely.
APOMORPHINE
- Action to be taken: Caution, monitor CNS side effects
- RationaleThe route of metabolism in humans is not known. Potential routes of metabolism in humans include sulfation, N-demethylation, glucuronidation and oxidation. In vitro, apomorphine undergoes rapid autooxidation. There have been reports in the literature of patients treated with APOKYN subcutaneous injections who suddenly fell asleep without prior warning of sleepiness while engaged in activities of daily living. Somnolence is commonly associated with APOKYN, and it is reported that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, even if patients do not give such a history. Adding ethanol to both high and low doses of THC increased impairment on several measures, as well as adding to subjective experiences . In a study by Johnstone et al. THC potentiated the sedative and respiratory depressant effects of the opioid oxymorphone. A second study in man confirmed an additive effect when THC was combined with secobarbital.
References
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