A Phase 1 Trial of Pharmacologic Interactions between Transdermal Selegiline and a 4-hour Cocaine Infusion

Debra S Harris; Thomas Everhart; Peyton Jacob III; Emil Lin; John E Mendelson; Reese T Jones

Disclosures

BMC Clin Pharmacol. 2009;9:1-18. 

In This Article

Abstract and Background

Abstract

Background: The selective MAO-B inhibitor selegiline has been evaluated in clinical trials as a potential medication for the treatment of cocaine dependence. This study evaluated the safety of and pharmacologic interactions between 7 days of transdermal selegiline dosed with patches (Selegiline Transdermal System, STS) that deliver 6 mg/24 hours and 2.5 mg/kg of cocaine administered over 4 hours.
Methods: Twelve nondependent cocaine-experienced subjects received deuterium-labeled cocaine-d5 intravenously (IV) 0.5 mg/kg over 10 minutes followed by 2 mg/kg over 4 hours before and after one week of transdermal selegiline 6 mg/24 hours. Plasma and urine were collected for analysis of selegiline, cocaine, catecholamine and metabolite concentrations. Pharmacodynamic measures were obtained.
Results: Selegiline did not change cocaine pharmacokinetic parameters. Selegiline administration increased phenylethylamine (PEA) urinary excretion and decreased urinary MHPG-sulfate concentration after cocaine when compared to cocaine alone. No serious adverse effects occurred with the combination of selegiline and cocaine, and cocaine-induced physiological effects were unchanged after selegiline. Only 1 peak subjective cocaine effects rating changed, and only a few subjective ratings decreased across time after selegiline.
Conclusion: No pharmacological interaction occurred between selegiline and a substantial dose of intravenous cocaine, suggesting the combination will be safe in pharmacotherapy trials. Selegiline produced few changes in subjective response to the cocaine challenge perhaps because of some psychoactive neurotransmitters changing in opposite directions.

Background

The acute administration of cocaine produces euphoria and chronic administration produces hedonic dysregulation, which are both believed to be mediated by dopaminergic systems.[1] Chronic cocaine use-induced dysregulation of the brain dopamine system may mediate cocaine reward, craving and relapse.[2] One approach to treating this dysregulation has been the use of medications that increase dopamine activity. Selegiline, a relatively selective monoamine oxidase (MAO)-B inhibitor at lower doses has been investigated as a pharmacological treatment for cocaine dependence.

Selegiline, approved for the treatment of Parkinson's Disease, inactivates MAO-B irreversibly and increases its substrate dopamine in the synapse; reactivation requires at least one to two weeks.[3] A placebo-controlled, double-blind treatment trial using selegiline 10 mg per day orally for eight weeks (a dose in the range selective for MAO-B) suggested selegiline may be useful for the treatment of cocaine dependence, based on decreases in quantitative urine concentrations of the metabolite (benzoylecgonine) and improved self- and investigator-rated global clinical status (prepublication data, NIDA-MDD). However, a later study using the selegiline transdermal system (STS) was not as encouraging.[4]

Transdermal selegiline is well tolerated, avoids the erratic bioavailability from extrahepatic metabolism in the gut[5] and extensive first pass metabolism,[6] may decrease the risk of hypertensive crisis ("cheese effect"), and may decrease some of the side effects by decreasing generation of selegiline's major metabolites, l-methamphetamine and l-amphetamine.[7]

Several studies have evaluated the safety of selegiline and cocaine co-administration.[8–11] These studies all used a single dose of 20 or 40 mg of intravenous (IV) cocaine for each cocaine challenge session following daily dosing of selegiline orally[8–10] or transdermally.[11] Our study also evaluated the pharmacologic interactions between 7 days of patches delivering 6 mg/24 hours of selegiline transdermally and cocaine. However, because persons with cocaine dependence often use repeated larger doses of cocaine during a period of use, we administered a larger dose of cocaine (2.5 mg/kg) as an infusion over a longer period of time (4 hours) to more closely simulate the doses and duration of use reported by many patients. This increased exposure to cocaine allowed assessment of drug-drug interactions at drug levels likely to be encountered in clinical practice.

Because of the importance of dopamine to the rewarding effects of drugs, concentrations of dopamine or its metabolites may help explain changes in the subjective effects of cocaine given during selegiline administration. Homovanillic acid (HVA) is a major metabolite of dopamine released in the brain, and although plasma concentrations of this metabolite are influenced by other factors, it may be a useful indicator of brain dopamine activity.[12]

In addition to inhibiting the reuptake of dopamine, cocaine is also a potent inhibitor of norepinephrine reuptake. Measurement of urinary 3-methoxy-4-hydroxyphenylglycol (MHPG), the main excretory product of norepinephrine, has been used as an index of the release of brain norepinephrine. Because MHPG is conjugated to MHPG-S in the central nervous system prior to excretion[13] we chose to analyze for only the conjugated MHPG-S in order to more specifically focus on brain norepinephrine activity.

Cocaine would be expected to increase brain norepinephrine turnover with a subsequent increase in urine levels of MHPG-S. Acute doses of selegiline should also increase synaptic norepinephrine and corresponding urinary MHPH-S levels, unless significant MAO-A inhibition is present, preventing the metabolism of norepinephrine to MHPG. However, with sustained selegiline dosing, norepinephrine depletion could occur and MHPG-S levels could decline to baseline (or even below). Assessing the effects of cocaine before and after treatment with selegiline could provide information about changes in cocaine-induced norepinephrine regulation.

It is not clear how much, if any, MAO-A inhibition occurs after treatment with 6 mg/24 hours of STS or what risk this poses, particularly when other drugs or foods that increase catecholamine activity are co-administered. Hypertensive crises have been reported with MAO-A inhibitors and sympathomimetic amines, such as phenylpropanolamine.[14] The interactions between MAO-A inhibitors and cocaine administered are largely unexplored. However, cocaine during use of a MAO-A inhibitor did not produce a hypertensive crisis in a preclinical study[15] and a case report.[16] Since hypertensive crises do not occur in every case, surrogate measures would be important. Therefore, measurement of dopaminergic and noradrenergic tone may be important in predicting toxic events. We measured dopaminergic tone with the surrogate marker of plasma HVA, the major brain metabolite of dopamine, and serum levels of prolactin, a hormone whose secretion is inhibited by dopamine. The surrogate for noradrenergic tone was urine concentrations of MHPG-S. In order to assess the degree of MAO-A and MAO-B inhibition, we assayed concentrations of a substrate of MAO-B, phenylethylamine (PEA).[17–19] PEA would be expected to increase with MAO-B inhibition, and concentrations of MHPG-S, which is a metabolite of norepinephrine produced by MAO-A primarily in the brain,[20] would be expected to decrease. Since MHPG-S is both an indicator of brain norepinephrine activity and a metabolite of MAO-A, the pattern of change (after initiation of selegiline administration and after cocaine administration) can help define mechanistic interactions.

This paper reports pharmacological interactions between cocaine and selegiline. We describe effects on dopamine, norepinephrine, MAO-A, and MAO-B activity, and on physiological and subjective effects of cocaine before and after one week of transdermal selegiline.

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