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A Selegiline Transdermal System (STS) is under development for indications which may not be optimally or safely treated with oral selegiline. Studies were conducted to evaluate the in vitro penetration and skin metabolism of selegiline in order to better understand the toxicological findings and the observed plasma levels of selegiline and its metabolites in animals and man.In vitro penetration studies were conducted in four different species (male hairless mice, male and female rats, female dog and male Micropig) and compared to human skin. In another study, viable human skin was used to estimate the extent of metabolism of selegiline by human skin using Franz diffusion cells.Results indicated that female dog and male Micropig skin were reasonable animal models for 24 hour in vitro selegiline penetration through human skin. Penetration of selegiline through rat skin and hairless mouse skin was 2-fold and 3-fold higher than through human skin, respectively. Metabolism was negligible in human skin. Selegiline metabolites (L-methamphetamine and N-desmethylselegiline but not L-amphetamine) were detected at all time points but the extent of selegiline metabolism was negligible. The cumulative 24 hour in vitro selegiline permeation from a 1.83 mg/cm2 STS through human skin was 5.0 mg. This was similar to the in vivo permeation in humans as assessed by residual patch analysis.The similarity of dog and human skin permeation results support the use of the dog as a species for evaluating the toxicology of transdermally-administered selegiline. Selegiline is not metabolized cutaneously and hence the metabolic profile following STS administration is likely due to hepatic metabolism only.

The absorption and disposition of selegiline (SEL) and its metabolites N-desmethylselegiline (DMS), L-methamphetamine (MET), and L-amphetamine (AMP) were assessed in 8 healthy male volunteers at proximal and distal regions of the intestine relative to oral administration (in the stomach) to determine if intestinal site dependence contributed to the erratic oral absorption of selegiline hydrochloride which is manifest as low and variable bioavailability.An open-label, four-way crossover, single dose pharmacokinetic study comparing the bioavailability of 10 mg selegiline hydrochloride administered to healthy young males as a solution by the oral route (in the stomach) and by a nasoenteric tube to the following three sites: duodenum, jejunum and terminal ileum was conducted. Infusions were administered over a 1 minute interval and a two week washout was observed between treatments. Samples were taken over 96 hours and analyzed by LC/MS/MS.Selegiline exposure was greatest following administration to the stomach (approximately 150%duodenum or jejunum) and least in the terminal ileum (approximately 33% less than duodenum or jejunum). Duodenal and jejunal sites were equivocal based on selegiline absorption and subsequent metabolism. While both AMP and MET exposure was equivalent at all dosing sites, DMS exposure was less (approximately 18%) at the terminal ileum.The oral absorption of selegiline is neither permeability-limited or intestinal site-dependent. Stomach absorption may bypass presystemic metabolism. The reduced DMS exposure at the terminal ileum is consistent with the theorized presystemic formation of DMS via luminal P450 enzymes and the density of these enzymes in the duodenum and jejunum relative to the ileum. AMP and MET metabolites were insensitive to dosing site consistent with their hepatic formation. The true magnitude of these effects would require multiple dosing as single dose pharmacokinetics do not predict the extent of multiple dose selegiline exposure.

A Microsoft Windows-based front-end, NM-Win, has been written to provide a more user-friendly environment to do nonlinear mixed effect modeling with the NONMEM program. NM-Win utilizes an object-oriented interface design which allows users to view and edit control, PRED, and/or data files using Windows Notepad. In addition, calls made to the Microsoft FORTRAN compiler and linker which generate the final NONMEN executable are performed simply by clicking the "Run NONMEN" button. During the executive step, interactions can be viewed in a window to check the progress of the run. Errors encountered while NONMEN or NM-TRAN is running are brought to a window for ease in debugging. Advanced options allow the user the flexibility of compiling user-written PRED files and creating linker response files. While the PC platform is not optimal for large data set or complex models, it does permit easier debugging and offers multitasking while Windows is running.

The pharmacokinetics and pharmacodynamics of L-703,014, a fibrinogen receptor antagonist, have been examined in the dog. An analytical method which utilizes methanol precipitation of dog plasma proteins followed by HPLC with an automated column switching technique using the chemical analogue L-704,326 as internal standard was developed for the determination of L-703,014 in dog plasma. The compound was not metabolized in the dog and was eliminated in the kidneys and into bile. Of the administered dose, 68.9 +/- 1.3% (i.v.) and 80.5 +/- 11.9% (p.o.) were recovered in the feces; 20.3 +/- 1.3% (i.v.) and 2.2 +/- 0.2% (p.o.) were recovered in the urine by 72 hr. L-703,014 was 23 +/- 3.4% bound in dog plasma protein and the mean ratio of plasma/whole blood was 1.22 +/- 0.05. The mean terminal half-life was 118 +/- 36 min, the mean steady-state volume of distribution was 0.61 +/- 0.22 L/kg, and the mean plasma clearance was 8 +/- 2 mL/min/kg. Ex vivo platelet aggregation measurements were made by inducing platelet aggregation with 10 micrograms/mL collagen in the presence of 1 microM epinephrine as an agonist. The mean C50 was 44.4 +/- 6.0 ng/mL, and the mean Hill coefficient was 1.5 +/- 0.3. The mean bioavailability was 4.9 +/- 1.4% in dogs administered 2.0 mg/kg (p.o.).