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PHARMACOKINETICS |
From Somerset Pharmaceuticals Inc, Tampa, Florida (Dr Azzaro, Ms Kemper); Gwynedd Pharmaceutical Consultants, Gwynedd Valley, Pennsylvania (Dr Ziemniak); Bristol-Myers Squibb Co, Plainsboro, New Jersey (Dr Campbell); and Mercer University Southern School of Pharmacy, Atlanta, Georgia (Dr VanDenBerg).
Address for correspondence: Albert J. Azzaro, PhD, AJA PharmaServices, 502 Sea View Drive, Tarpon Springs, FL 34689; e-mail: ajazzaro{at}aol.com.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Selegiline • transdermal • oral • pharmacokinetics • bioavailability
-dimethyl-N-2-propynylphenethylamine; (-)deprenyl] is an irreversible inhibitor of MAO that is administered orally as an adjunct to levodopa in the treatment of late-stage Parkinson disease.2,3 At the approved oral dosage of 5 mg twice daily, selegiline is a preferential inhibitor of MAO-B and does not require dietary restrictions that are generally imposed on nonselective MAO inhibitors (MAOIs).4-6 Dietary modifications are necessary during treatment with the traditional, nonselective MAOIs to avoid the risk of hypertensive crisis following the ingestion of foods containing high concentrations of tyramine.7,8 Tyramine is an indirect-acting sympathomimetic that has the potential to cause an acute elevation in blood pressure following its systemic absorption, resulting in hypertensive crisis and damage to the central nervous system (CNS) (eg, stroke).7,9 MAO-A acts as an intestinal barrier to the systemic absorption of dietary tyramine.4,10 Small, published clinical trials have also demonstrated the potential use of selegiline as an antidepressant therapy; however, the oral doses required for this therapeutic effect are 3 to 6 times greater than those approved for the treatment of Parkinson disease.11-13 At these higher, off-label, oral doses, selegiline no longer maintains selective inhibition of MAO-B at peripheral tissue sites and, with the additional inhibition of MAO-A in the intestinal mucosa, carries the risk of hypertensive crisis associated with dietary tyramine ingestion.6,14
Recently, a transdermal formulation of selegiline (selegiline transdermal system [STS] [1 mg selegiline/1 cm2]) has been approved as a once-daily treatment of major depressive disorder (MDD). The STS is manufactured in doses of 6, 9, and 12 mg/24 h. The STS was developed to avoid the extensive rate of first-pass metabolism (>90%) of orally administered selegiline. In this regard, selegiline is metabolized by a variety of cytochrome P450 hepatic pathways to N-desmethylselegiline, R(-)-methamphetamine, and R(-)-amphetamine. Accordingly, the STS permits administration of the required high antidepressant concentrations of selegiline to the CNS while maintaining the intestinal barrier to dietary tyramine, thus avoiding the risk of tyramine-induced hypertensive crisis. The preferential effects of transdermally administered selegiline on CNS MAO-A and MAO-B inhibition have been demonstrated in animal studies.15,16 In addition, the absence of a clinically meaningful increase in the cardiovascular sensitivity to orally administered tyramine has been demonstrated in human pharmacology studies conducted with the 6-mg/24-h STS.17 The 6-mg/24-h STS has demonstrated antidepressant efficacy as both acute18,19 and maintenance therapy.20 Accordingly, these clinical safety and efficacy data have supported the approval of the 6-mg/24-h STS by the US Food and Drug Administration (FDA) for treatment of MDD without dietary modifications. However, because of limited safety data, the 9- and 12-mg/24-h doses of the STS require the adherence to a modified tyramine diet.
The current study was conducted during the STS development program to characterize the single-dose pharmacokinetics (PK) and absolute bioavailability of selegiline administered by the 6-mg/24-h STS in healthy volunteers. Selegiline bioavailability was based on the intravenous (IV) administration of selegiline HCl (10 mg/24 h) as the reference standard. The selegiline PK and relative exposure obtained following treatment with the STS were also compared with those obtained after a single 10-mg oral dose of selegiline HCl.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Materials
The STS (1 mg selegiline/1 cm2 patch; EMSAM) was manufactured by Mylan Technologies (St Albans, Vermont) and supplied in a delivered dose of 6 mg/24 h (20-cm2 patch). Selegiline HCl 5-mg capsules (Eldepryl) were supplied by Somerset Pharmaceuticals Inc (Tampa, Florida). The IV selegiline HCl infusion solution (10 mg/L 0.9% NaCl) was prepared at the clinical site (PPD Development, Austin, Texas) by a registered pharmacist, documenting preparative methods, analytical accuracy, negative pyrogenicity, and positive sterility. Examination of the preinfusion values (time 0) revealed an overall mean recovery value of 98.5%, confirming the accuracy of the formulation.
Study Design
This was a randomized, open-label, single-center, single-dose, 3-way crossover study. Each subject was randomized to 1 of 3 treatment groups (see below). Treatment periods consisted of a single STS (6 mg/24 h; 20-cm2 patch), a single 10-mg selegiline HCl dose (two 5-mg selegiline HCl capsules; 8.37 mg selegiline), or an IV infusion of selegiline HCl (10 mg/24 h; 0.7 mL/min; 8.37 mg/24 h selegiline). An interval of 8 days was maintained between each treatment period. Subjects were confined to the study site for 5 days during each treatment period. Blood and urine samples were drawn at scheduled times to assess concentrations of selegiline and its metabolites. The study was performed without tyramine dietary restrictions.
Participants
Nonobese (defined as ±10% of desirable body weight for frame size), nonsmoking, healthy male volunteers 18 to 45 years of age willing and able to provide informed consent were eligible for enrollment. Subjects were excluded for medical history that included any cardiovascular disease or disorder including cardiac arrhythmia or orthostatic hypotension; any skin abnormalities that might interfere with the conduct or interpretation of the study; any gastrointestinal disease or digestive disorder; any known hypersensitivity or related hypersensitivity to any drug used in the study; any clinically significant neurological, pulmonary, hepatic, renal, hematologic, endocrine, and/or metabolic disease or disorder; any psychiatric illness; any substance abuse or addiction; and any significant allergy, especially involving dermal manifestations.
Subjects were also excluded if they required or used any prescription medications within 35 days of study initiation or anticipated use of any CNS medication such as meperidine, tricyclic antidepressants, selective serotonin reuptake inhibitors, or serotonin norepinephrine reuptake inhibitors; used any over-the-counter (OTC) medication within 14 days of study drug administration (including herbal remedies); consumed a diet that was not considered within normal limits for amounts of protein, carbohydrates, and fat, as judged by the investigator (eg, vegetarians); consumed alcohol or caffeine/xanthine-containing drinks or foods within 24 hours of study initiation (including any types of wines, herbal tea, caffeinated or decaffeinated beverages, and grapefruit juice); had a history of smoking in the previous 6 months; tested positive for cannabinoids, cocaine, amphetamines, barbiturates, opiates, benzodiazepines, blood alcohol, HIV antibodies, or HbsAg; participated in a clinical investigation within the past 45 days; donated blood (1 pint or greater) within 8 weeks prior to administration of study medication; or had any other condition that, in the investigator's opinion, placed the subject at greater than normal risk of developing complications.
Subjects were assigned numbers 01 to 12 according to the order of enrollment and randomized in blocks of 4 to 1 of 3 treatment groups according to a Latin square design. Replacement subjects were assigned a number starting with 13. Treatment assignments (see Table I) were made according to the protocol. Subjects were required to fast for 8 hours prior to dosing and 4 hours after dosing.
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Blood and Urine Sample Collection
Blood sample collection times were as follows:
Blood samples (7 mL) were drawn through an indwelling catheter from the arm contralateral to the site of STS application or the 10-mg selegiline HCl IV infusion. Each subject had a total of 57 blood samples taken and a minimum of 300 mL of blood drawn for the assay of plasma selegiline and its major metabolites.
All blood samples were drawn into an evacuated glass tube containing sodium heparin and centrifuged (rcf = 1315). Immediately after centrifuging, the plasma was transferred to polypropylene tubes and stored at or below -20°C. Plasma samples were shipped frozen to Phoenix International Life Sciences Inc (Montreal, Quebec, Canada) for analysis of selegiline and each of its major metabolites (see below).
For the determination of urine concentrations of selegiline and its metabolites, 0- to 24-hour urine samples were collected in a polypropylene container over a 5-day collection period from each volunteer at the following times during the study: -24 to 0 (predose), 0 to 24, 24 to 48, 48 to 72, and 72 to 96 hours relative to 0-hour drug administration. Subjects were instructed to provide a complete 24-hour specimen. Sample collection times of the first and last voids for each 24-hour collection were recorded. Collected urine samples were stored at 4°C (refrigerated) for the full 24-hour collection period. Upon completion, the volume excreted and pH values were recorded. A 50-mL aliquot of each 24-hour urine collection was obtained, frozen at or below -20°C, and then shipped for analysis (Phoenix International Life Sciences Inc; see below).
Dosing Solution (IV) and Patch Residual Concentrations
Samples (2 mL) of the final IV selegiline HCl dosing solution were obtained immediately prior to administration and at the end of the 24-hour infusion period to calculate the actual dose administered to each subject and to ensure the stability of the preparation over the 24-hour period, respectively. To determine the dose of selegiline administered by the transdermal route, each transdermal patch (STS) was collected following the 24-hour dosing period and returned to its original pouch for residual selegiline determination. All infusion aliquots and collected STSs were properly labeled, frozen at or below -20°C, and shipped for selegiline analysis (PPD Development, Middleton, Wisconsin; see below).
Analytical Methodology
Plasma and urine samples were assayed for selegiline and its 3 major metabolites by Phoenix International Life Sciences Inc, with a highly sensitive, validated assay using high-performance liquid chromatography (LC) separation and tandem mass spectrometry (MS) for detection (LC/MS/MS) and amitriptyline as the internal standard. Briefly, plasma and urine samples were liquid/liquid extracted with 1-chlorobutane, evaporated to dryness, and reconstituted in methanol for analysis. The LC separation was performed on a 33 x 4.6-mm (3 µm) LC-CN analytical column (SUPELCOSIL) operated at room temperature. The mobile phase was a mixture of methanol, 0.025 M ammonium acetate, and water (86:2:12, by volume), delivered at a flow rate of 1 mL/min. Detection was performed using a SCIEX MS/MS atmospheric pressure ionization spectrometer, in the multiple-reaction monitoring mode. The following transition mass-to-charge ratios (m/z) were monitored: 278.3 to 191.2 (internal standard, amitriptyline), 188.3 to 91.1 (selegiline), 174.1 to 91.1 (N-desmethylselegiline), 150.2 to 61.1 (R(-)-methamphetamine), and 136.3 to 91.1 (R(-)-amphetamine). The approximate assay calibration range in plasma was 25 to 8000 pg/mL for selegiline, 50 to 15 000 pg/mL for N-desmethylselegiline, 100 to 15 000 pg/mL for R(-)-amphetamine, and 100 to 15 000 pg/mL for R(-)-methamphetamine. Interassay accuracy was between 96% and 107%, and the interassay precision (expressed as the percentage coefficient of variation) was between 3.0% and 15.0% for all analytes.
Aliquots of the IV selegiline HCl dosing solution and the residual content of the transdermal selegiline patches, following the 24-hour subject application, were assayed for selegiline by PPD Development (Middleton, Wisconsin) with a highly sensitive, validated assay using high-performance LC separation, UV detection (205 nm), and selegiline HCl as the reference standard. Briefly, STS patches or aliquots of the IV selegiline HCl dosing solution were extracted in methanol, sonicated, and diluted in mobile phase to a theoretical concentration of 10 µg/mL selegiline. The LC separation was performed on a 75 x 4.6-mm (3.5 µm) Mac-Mod Zorbax SB C-18 reverse-phase analytical column (Agilent, Chadds Ford, Pennsylvania) operated at 35°C. The mobile phase consisted of a mixture of 50 mM potassium phosphate (pH 3.5), acetonitrile, and methanol (80:15:5 by volume), delivered at a flow rate of 1 mL/min. Detection was performed with a UV detector (205 nm). Selegiline HCl was used as the reference standard at a concentration of 10 µg/mL and corrected for free base equivalence. The area responses for the diluted extracts and the reference standard were within the validated range of the analytical method. Each sample was assayed in duplicate and the average value reported. Interassay accuracy was between 99.6% and 100.7%, and the interassay precision (expressed as the percentage coefficient of variation) was between 0.3% and 1.1%.
Pharmacokinetic and Statistical Analysis
A noncompartmental approach was used for PK data analysis. Plasma and urine concentration data and the estimated PK parameters from the 12 subjects who completed all 3 treatment regimens were summarized using arithmetic means and percentage coefficients of variation (%CVs). All computations were made using actual sampling times. The following noncompartmental PK parameters were estimated from the plasma concentration profiles for each subject: area under the plasma concentration-time curve (AUC0-24, AUC0-t), calculated by the linear trapezoidal rule; AUC0-
, calculated as AUC0-t + Ct/Kel; maximum plasma concentration (Cmax) over the entire sampling phase, directly obtained from the experimental data of plasma concentration versus time curves, without interpolation, over the dosing interval 
; time to attain Cmax (tmax); time interval from dosing to time of first measurable plasma concentration (tlag); apparent elimination rate constant (Kel); apparent elimination half-life, calculated as 0.693/Kel (t
); mean residence time (MRT = AUMC0-t/AUC0-t, where AUMC0-t = area under the first-moment concentration-time curve, time zero to last measurable concentration); and apparent plasma clearance (CL/F = dose/AUC0-t).
The plasma ratio of each metabolite to selegiline (M/P) was calculated from AUC values. Renal clearance (CLR) was determined from the amount of analyte excreted/AUC. The apparent fraction excreted was calculated from the amount of analyte excreted/dose (as free base). All PK parameters were derived using validated programs prepared with PC-SAS Version 6.12 (SAS Institute, Cary, North Carolina). Plots representing mean (%CV) values were generated using both Sigma Plot Version 5.0 and PC-SAS Version 6.12 (SAS Institute).
The absolute bioavailability of selegiline administered by transdermal patch (STS) (F = (AUC)T (Dose)IV/(AUC)IV (Dose)T) or oral selegiline capsule (F = (AUC)po (Dose)IV/(AUC)IV (Dose)po) was calculated from dose-normalized AUC0-t and AUC0- values using IV selegiline as the reference standard. All selegiline doses were converted to the free base. The relative extent of exposure between transdermal (STS) and oral selegiline administration (F = (AUC)T (Dose)po/(AUC)po·(Dose)T) was also calculated from dose-normalized AUC0-t and AUC0- values.
The apparent dose-normalized PK parameters of interest (AUC and Cmax) were compared using a 3-way analysis of variance (ANOVA) model with terms for sequence, subject within sequence, treatment, and period effects (PROC GLM and PROC MIXED, SAS Version 6.12, SAS Institute). The subject-within-sequence effect was used as the error term to evaluate the sequence effect at the = .10 level of significance. The mean square error (MSE) of the model was used to evaluate the treatment and period effects at the = .05 level of significance. Pharmacokinetic parameter ratios were generated using the least squares means of the estimates obtained from the ANOVA model.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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The metabolite mean plasma concentration-time profiles following treatment with each of the selegiline formulations are shown in Figure 2. The pattern of selegiline metabolite formation was very similar during treatment with the STS or IV infusion. However, following oral selegiline dosing, an earlier formation of the metabolites was observed prior to and during the time of the rapid decline in selegiline levels.
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for all analytes following the oral selegiline dose was replaced with the AUC0-t. Failure to perform the AUC0- calculation was based on the inability to accurately determine the apparent elimination rate constants (Kel) of each analyte for the oral dose.
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Examination of the AUC0-t values for selegiline and its metabolites illustrates the extensive metabolism of selegiline when administered by oral dosing compared with the IV and transdermal routes. Without dose normalization, the extent of selegiline exposure during oral dosing was approximately 10 times less than observed during STS treatment and approximately 22 times less than following IV infusion (see Table IV for dose-normalized comparison). In addition, a high value for the apparent oral selegiline clearance (CL/F) was observed. By contrast, metabolite exposure was greatly reduced during STS or IV dosing. The differences in the rate of selegiline metabolism between administration routes were demonstrated by the metabolite to parent (selegiline) drug AUC0-t ratios (AUC0-t M/P). An AUC0-t M/P ratio of approximately 2.3 or less was obtained for N-desmethylselegiline, R(-)amphetamine, and R(-)methamphetamine after STS and IV administration compared with AUC0-t M/P values ranging from 86 to 903 after oral administration.
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Examination of the AUC0-t M/P ratios, MRT, and the tlag of selegiline and its metabolites for the 3 formulations suggests that with each form of selegiline delivery, R(-)methamphetamine was the major metabolite formed, followed by R(-)-amphetamine and N-desmethylselegiline. In addition, examination of the tmax, MRT, and tlag values suggests that the metabolites were formed sequentially. During oral, transdermal, and IV dosing, the order of plasma analyte appearance was selegiline, N-desmethylselegiline, R(-)methamphetamine, and R(-)amphetamine.
The half-life (t) of selegiline and its metabolites after IV and STS dosing was similar and ranged from 15 to 25 hours. However, a shorter half-life was observed after oral selegiline dosing (9-15 hours). This shorter half-life was likely a function of the lower concentrations of analytes and the inability to accurately measure the Kel of each analyte during the terminal or "beta" phase of the elimination curve.
Renal excretion did not contribute significantly to the elimination of selegiline or its N-desmethylselegiline metabolite. The average apparent excretion (%Fe) of selegiline and N-desmethylselegiline was <1% after IV, oral, or STS administration. However, during the period of urine collection (0-96 hours), significant amounts of both amphetamine metabolites were eliminated by renal excretion. In this regard, the %Fe values for R(-)amphetamine and R(-)methamphetamine were 
13% (11%-14%) and 30% (26%-33%), respectively, after IV and oral administration, and lower values (ie, 7.2% for R(-)amphetamine and 17.6% for R(-)methamphetamine) were observed for both of these metabolites after STS administration. For all treatments, renal clearance of selegiline and N-desmethylselegiline (<1 L/h) was low as compared with the glomerular filtration rate of 7.50 L/h. By contrast, R(-)amphetamine and R(-)methamphetamine exhibited renal clearance values comparable with the glomerular filtration rate for all treatments. The mean value for the urine pH was 6.31 ± 0.35 and was within the normal range of 4.5 to 8.0.
Bioavailability of Selegiline: A Comparison of STS Versus Oral Selegiline Capsules
The assay results for the 24-hour residual content of each of the worn transdermal patches (STS) were used to calculate the apparent selegiline dose administered to each subject. The amount of selegiline released (apparent dose administered expressed as free base) from the STS ranged from 3.21 to 6.60 mg/24 h (mean, 4.78 ± 1.05 mg/24 h). The delivered selegiline dose value was used for dose normalization of AUC and Cmax values in the calculation of bioavailability for the STS. For IV and oral selegiline dosing, the apparent dose administered as the free base was 8.37 mg/24 h (the mean concentration for the selegiline IV solution, 8.15 ± 1.27 µg/L, was found to be 97.38% ± 15.22% of 8.37 µg/L). Accordingly, 8.37 mg/24 h was used for the dose normalization calculation of PK values following IV and oral selegiline dosing.
The least squares mean, dose-normalized PK parameters (AUC0-, AUC0-t, and Cmax), and the ratios of treatment comparisons for selegiline are presented in Table IV. Comparisons of the dose-normalized PK values demonstrate the differences between the STS and oral selegiline capsules regarding the relative extent of exposure (AUC) and Cmax of selegiline. In this regard, AUC value ratios demonstrate that the extent of selegiline exposure is approximately 17 times greater during STS treatment compared with an equivalent dose of oral selegiline. In addition, Cmax ratios show that the maximum concentration of selegiline achieved during treatment was approximately 1.7 times greater during STS treatment compared with oral dosing.
The absolute selegiline bioavailability was determined from the apparent dose-normalized PK parameter ratios using IV dosing as the reference standard. The absolute bioavailability of selegiline administered by the STS, based on AUC0- and AUC0-t, was 73.7% and 73.4%, respectively, of the IV dosing. The peak selegiline concentration (from the ratio of the Cmax values) was 83.6% of the IV route of administration. By contrast, the absolute oral selegiline bioavailability (based on AUC0-t) was only 4.4%, and the peak concentration was 48.6% of IV dosing.
Statistical comparisons (ANOVA) of the data indicated a significant (P < .05) treatment effect for the apparent dose-normalized PK parameters for selegiline and its metabolites. However, no significant sequence effects were observed for any of the PK parameters examined.
Safety
A summary listing of adverse events (AEs) that occurred during the study is presented in Table V. Seven (53.8%) of the 13 subjects reported a total of 10 AEs. All the reported AEs were considered to be mild in severity, none required treatment, and all AEs resolved without sequelae. Five (38.5%) of the 13 subjects reported a total of 6 AEs considered by the investigator to be at least remotely related to study medication. No deaths, discontinuations due to AEs, or serious adverse experiences (SAEs) were reported during the study period. Finally, the results of all clinical laboratory tests were unremarkable, and vital signs remained within the normal range.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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The safety results of this study demonstrated that selegiline was well tolerated regardless of the route of administration. These safety findings are consistent with previously published data showing that selegiline is safe and well tolerated when administered within the range of approved oral or transdermal doses.18-21,28,29 In contrast, the PK of selegiline differed greatly between the routes of administration. Selegiline administered by transdermal patch (STS) produced a plasma selegiline concentration-time profile that was qualitatively similar to IV infusion but with a lower overall extent of exposure. However, oral dosing produced a rapid peak in plasma selegiline that occurred within 1 hour and rapidly declined over the time course. In addition, the extent of oral selegiline exposure was approximately 17 times lower than observed during equivalent transdermal (STS) dosing and approximately 22 times lower than observed during the IV selegiline infusion. Furthermore, peak selegiline concentration following STS dosing was nearly 2-fold greater than that seen with equivalent oral dosing.
The differences observed in the plasma selegiline concentration-time curve following the oral and transdermal routes of administration are consistent with a rapid absorption and high rate of first-pass metabolism during oral selegiline dosing. A review of the dose-normalized AUC0-t values for each of the selegiline metabolites demonstrates that compared with oral dosing, selegiline metabolite exposure was reduced by approximately 50% during treatment with the STS. In addition, the large metabolite/selegiline (M/P) ratio that ranged from 86 to 903 after oral dosing was reduced to 
2.3 after treatment with the STS. Finally, the shorter tlag and tmax for each of the selegiline metabolites, as well as the higher CL/F and lower bioavailability observed with oral selegiline compared with the STS, all support a high rate of first-pass metabolism for selegiline during oral dosing. These results are consistent with the work of others who have reported a significant first-pass effect with orally administered selegiline.22,23,26 Furthermore, our results are qualitatively similar to the early PK data in healthy elderly male and female subjects reported by Barrett et al23 and in young healthy male subjects reported by Rohatagi et al,30 both obtained with a prototype selegiline transdermal patch.
Differences between administration routes were also noted in the degree of variability (%CV) observed in the selegiline PK data. Oral dosing produced the highest degree of variability that was likely related to the high rate of first-pass metabolism, the limits of assay sensitivity, and the small number of subjects studied. The avoidance of the first-pass effect following dosing with the STS reduced the variability in selgiline exposure by approximately 50%. Data from other studies in the STS development program have demonstrated that this degree of variability in selegiline exposure can be further reduced by proper and consistent patch application. Thus, it suggests that transdermal delivery of selegiline also provides a more consistent exposure level among individuals that may have clinical importance for safety and efficacy with this agent.
The data presented in this article clearly demonstrate that the selegiline metabolites were formed in a sequential manner. Moreover, although the extent of metabolism was greatly reduced during STS or IV treatment, the sequence of metabolite formation was unaltered by route of administration. During STS, IV, or oral dosing, R(-)-methamphetamine remained the major selegiline metabolite, and the order of metabolite appearance was N-desmethylselegiline, R(-)-methamphetamine, and R(-)-amphetamine, respectively (see tmax + tlag).
As expected, the renal clearance of selegiline and its metabolites also remained unchanged regardless of the route of administration. For all treatments, renal clearance of selegiline and N-desmethylselegiline (<1 L/h) was low, suggesting that renal excretion plays a minimal role in their elimination from the body. In addition, the low renal clearance of these compounds, as compared with the glomerular filtration rate of 7.50 L/h, suggests that both of these compounds are subject to tubular reabsorption. These findings are consistent with selegiline being a weak base with a pKa of 7.5, a molecular weight of 187.3, and a calculated octanol/water partition coefficient of 3.4.31 By contrast, R(-)amphetamine and R(-)methamphetamine exhibited renal clearance values (7.3-8.7 L/h) that were similar to the glomerular filtration rate. These data, along with the moderate %Fe values for the amphetamine metabolites, suggest that renal excretion plays a primary role in their elimination.
A major objective of the present study was to determine the absolute bioavailability of selegiline when administered by the STS. The absolute oral bioavailability of selegiline was also obtained for comparative purposes. When the STS was examined, the absolute bioavailability, based on dose-normalized AUC values, was approximately 73% of the IV selegiline dosing. By contrast, the absolute oral bioavailability of selegiline was only 4% of the IV selegiline dosing. This low degree of absolute oral bioavailability was expected and consistent with the low bioavailability values (10%) suggested by others.22,26 This low degree of absolute oral bioavailability is also consistent with extensive first-pass clearance as reported by others and confirmed in this study.22,23,26 A high rate of hepatic cytochrome P450-dependent hepatic metabolism has been demonstrated for selegiline and its metabolites.22,32,33 Because of the extensive first-pass metabolism, the plasma metabolite concentrations far exceed those of selegiline following its oral administration.
The necessity of administering high oral doses of selegiline (30-60 mg/d)11-13 to patients with depression to achieve off-label antidepressant benefit is clearly associated with the high degree of first-pass metabolism and the limited systemic selegiline exposure as revealed in this study. Although the oral dosing of selegiline has limited utility, the results of the current study provide PK data that suggest clinical advantages of administering selegiline by the transdermal route for the treatment of major depressive disorder. Selegiline administration by transdermal patch (STS) avoids the first-pass effect and produces high, sustained, and more consistent selegiline exposure over a 24-hour dosing period, with an absolute bioavailability of approximately 73%. Accordingly, the transdermal route of administration, which provides antidepressant concentrations of selegiline to the CNS by administering as little as 6 mg selegiline/24 h,18-20 should promote reliable dosing and medication compliance and significantly reduce exposure to the metabolites R(-)amphetamine and R(-)methamphetamine. In addition, this method of selegiline administration avoids the high degree of gastrointestinal selegiline exposure necessary for oral off-label antidepressant dosing that is associated with significant gastrointestinal MAO-A inhibition and the risk of dietary tyramine-induced hypertensive crisis.6,14 In this regard, human tyramine challenge studies have demonstrated that a 6-mg/24-h antidepressant dose of the STS is without meaningful changes in cardiovascular sensitivity to orally administered tyramine.17
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CONCLUSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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