Integrated pharmacokinetic and metabolic modeling of selegiline and metabolites after transdermal administration

Biopharm Drug Dispos. 1997 Oct;18(7):567-84. doi: 10.1002/(sici)1099-081x(199710)18:7<567::aid-bdd49>;2-7.


Selegiline (SEL) is a selective, irreversible inhibitor of MAO-B, used in the treatment of Parkinson's disease, either alone or as an adjunct to L-DOPA. Selegiline hydrochloride (HCl) undergoes significant first-pass metabolism following oral administration. Transdermal delivery avoids the first-pass effect and provides greater and more prolonged levels of unchanged SEL and reduced levels of metabolites (N-desmethylselegiline (DES), L-amphetamine (AMP), and L-methamphetamine (MET) compared to the oral regimen. An integrated pharmacokinetic-metabolic model which predicts plasma concentrations of SEL and metabolites following a single 24 h application of a selegiline transdermal system (STS) is proposed. The model is based on the metabolic conversion of SEL to DES and MET and subsequently to AMP. The input function is described by a zero-order constant for the delivery of SEL from the STS system based on in vitro studies of penetration of SEL across human skin. The elimination-non-metabolic constants for each analyte account for the urinary elimination. Plasma concentration data from a pilot pharmacokinetic study in which six healthy male volunteers were administered single 24 h applications of a 1.8 mg cm2, 10 cm2 STS were used to examine this model. The coefficient of determination was 0.98 and model selection criterion was 3.4 for mean data fits, supporting the goodness of fit of the model. The pharmacokinetic parameters obtained by non-compartmental analysis were comparable to those predicted by a compartmental model. The model also predicted urinary recoveries for AMP and MET and negligible recovery for SEL and DES consistent with recent studies with the STS in which urine was collected. The metabolic conversion constant from SEL to DES was significantly lower than the conversion constant from SEL to MET, indicating that metabolism of SEL is primarily driven towards MET following transdermal administration. The metabolic conversion from MET to AMP was less than the conversion from DES to AMP. This simultaneous prediction of the SEL and metabolites is essential as the metabolic ratios have been linked to the neuroprotective effects of SEL. These findings support the proposed regional delivery advantage attributed to the transdermal route compared to the conventional therapy with the oral tablet. Future model applications may also help identify significant covariates (i.e. age, gender, and disease state) in upcoming clinical trials.

Publication types

  • Clinical Trial

MeSH terms

  • Administration, Cutaneous
  • Amphetamine / blood*
  • Amphetamines / blood*
  • Antiparkinson Agents / metabolism
  • Antiparkinson Agents / pharmacokinetics*
  • Area Under Curve
  • Humans
  • Male
  • Methamphetamine / blood*
  • Models, Biological
  • Monoamine Oxidase Inhibitors / metabolism
  • Monoamine Oxidase Inhibitors / pharmacokinetics*
  • Pilot Projects
  • Regression Analysis
  • Selegiline / metabolism
  • Selegiline / pharmacokinetics*


  • Amphetamines
  • Antiparkinson Agents
  • Monoamine Oxidase Inhibitors
  • Selegiline
  • Methamphetamine
  • desmethylselegiline
  • Amphetamine