Enhanced Topical and Transdermal Delivery of Antineoplastic and Antiviral Acyclic Nucleoside Phosphonate cPr-PMEDAP

Abstract

Transdermal or topical application of cPr-PMEDAP enabled by the permeation enhancer DDAK may provide an attractive alternative route of administration of this potent antitumor and antiviral compound.

Amino acid derivatives as transdermal permeation enhancers

“…Then, after reaching enzymatically active nucleated epidermis, its labile bond could be hydrolyzed, thus releasing known non-toxic compounds with much lower irritation potential. This approach to designing permeation enhancers resulted in the identification of highly potent enhancers with favorable properties, such as DDAIP [16], Transkarbam 12 (T12, [23,24]), tranexamic acid derivatives [25], and dodecyl 6-(dimethylamino)hexanoate (DDAK, [26][27][28], Fig. 1B).…”

The Acyclic Nucleoside Phosphonates (ANPs): Antonín Holý's Legacy

“…64 Transdermal and topical delivery of cPrPMEDAP was recently described. 65 The enzyme responsible for the conversion of cPrPMEDAP to PMEG was shown to be an hitherto unknown N 6 -methyl-AMP aminohydrolase. 66 GS-9191 has been further pursued for its utility in the topical treatment of HPV-associated lesions such as genital warts.…”

“…The antitumor potential of cPrPMEDAP was demonstrated in a choriocarcinoma model in rats . Transdermal and topical delivery of cPrPMEDAP was recently described . The enzyme responsible for the conversion of cPrPMEDAP to PMEG was shown to be an hitherto unknown N 6 ‐methyl‐AMP aminohydrolase .…”

Transdermal Delivery and Cutaneous Targeting of Antivirals using a Penetration Enhancer and Lysolipid Prodrugs

“…1) (13,14). This amino acid-based penetration enhancer increased skin flux of the structurally related ANPs adefovir by 179-fold (14,15) and cPr-PMEDAP by 61-fold (13). Furthermore, DDAK increased skin flux of theophylline by 17-fold, hydrocortisone by 43-fold, and indomethacin by 9-fold (16).…”

“…We have recently shown that certain enhancers can increase the absorption of ANPs by two orders of magnitude; one such enhancer is the amino acid derivative DDAK (dodecyl ester of 6-(dimethylamino)hexanoic acid, Fig. 1) (13,14). This amino acid-based penetration enhancer increased skin flux of the structurally related ANPs adefovir by 179-fold (14,15) and cPr-PMEDAP by 61-fold (13).…”