INTEGRATED PHARMACOKINETIC AND METABOLIC MODELING OF SELEGILINE AND METABOLITES AFTER TRANSDERMAL ADMINISTRATION

Selegiline (SEL) is a selective, irreversible inhibitor of MAO-B, used in the treatment of Parkinson's disease, either alone or as an adjunc t to L-DOPA. Selegiline hydrochloride (HCl) undergoes significant firs t-pass metabolism following oral administration. Transdermal delivery avoids the first-pass effect and provides greater and more prolonged l evels of unchanged SEL and reduced levels of metabolites (N-desmethyls elegiline (DES), L-amphetamine (AMP), and L-methamphetamine (MET)) com pared to the oral regimen. An integrated pharmacokinetic-metabolic mod el which predicts plasma concentrations of SEL and metabolites followi ng 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 b y a zero-order constant for the delivery of SEL from the STS system ba sed on in vitro studies of penetration of SEL across human skin. The e limination-non-metabolic constants for each analyte account for the ur inary elimination. Plasma concentration data from a pilot pharmacokine tic study in which six healthy male volunteers were administered singl e 24 h applications of a 1.8 mg cm(2), 10 cm(2) STS were used to exami ne this model. The coefficient of determination was 0.98 and model sel ection criterion was 3.4 for mean data fits, supporting the goodness o f fit of the model. The pharmacokinetic parameters obtained by non-com partmental analysis were comparable to those predicted by a compartmen tal model. The model also predicted urinary recoveries for AMP and MET and negligible recovery for SEL and DES consistent with recent studie s with the STS in which urine was collected. The metabolic conversion constant from SEL to DES was significantly lower than the conversion c onstant from SEL to MET, indicating that metabolism of SEL is primaril y driven towards MET following transdermal administration. The metabol ic conversion from MET to AMP was less than the conversion from DES to AMP. This simultaneous prediction of the SEL and metabolites is essen tial as the metabolic ratios have been linked to the neuroprotective e ffects of SEL. These findings support the proposed regional delivery a dvantage attributed to the transdermal route compared to the conventio nal therapy with the oral tablet. Future model applications may also h elp identify significant covariates (i.e. age, gender, and disease sta te) in upcoming clinical trials. (C) 1997 by John Wiley & Sons, Ltd.