       Document 0216
 DOCN  M9640216
 TI    Transdermal delivery of dideoxynucleoside-type anti-HIV drugs. 1.
       Stability studies for hairless rat skin permeation.
 DT    9604
 AU    Kim DD; Chien YW; Controlled Drug-Delivery Research Center, Rutgers,
       State; University of New Jersey, College of Pharmacy, Piscataway 08854,;
       USA.
 SO    J Pharm Sci. 1995 Sep;84(9):1061-6. Unique Identifier : AIDSLINE
       MED/96079215
 AB    The stability of dideoxynucleoside-type anti-HIV drugs in solution when
       in contact with hairless rat skin was investigated in order to study the
       feasibility of their transdermal delivery. The freshly excised dorsal
       region of hairless rat skin was mounted on Valia-Chien skin permeation
       cells, and both epidermis (donor) and dermis (receptor) were extracted
       with isotonic phosphate buffer (pH 7.4) at 37 degrees C for 24 h.
       Zalcitabine (DDC), didanosine (DDI), and zidovudine (AZT) were found to
       be stable in the extract of the epidermis at 37 degrees C for at least
       30 h. However, DDC and DDI degraded in the extract of the dermis
       following first-order kinetics at both 25 and 37 degrees C, while AZT
       was stable at 37 degrees C for at least 30 h. The degradation
       mechanism(s) of DDC and DDI was (were) studied by analyzing HPLC
       chromatograms and by evaluating the drug stability in the extract which
       was filtered to remove any microbes. An unidentified peak produced by
       DDC in the dermis extract did not appear when the drug was added to the
       filtered extract, which suggested a bacterial degradation of DDC. On the
       other hand, DDI was unstable even in the filtered extract and produced a
       degradation product which corresponded to hypoxanthine, which suggested
       that a cutaneous enzyme is also involved in the degradation of DDI. DDC
       was stabilized by the addition of 0.01% (w/v) of an antibacterial agent,
       such as thimerosal or gentamicin, in the receptor solution, while DDI
       was stabilized by 0.01% (w/v) purine nucleoside phosphorylase inhibitor,
       i.e., p-chloromercuribenzoic acid. These results show the importance of
       stability studies when designing skin permeation experiments using
       hairless rat since compounds with similar chemical structures can have
       different stability profiles when in contact with hairless rat skin.
 DE    Administration, Cutaneous  Animal  Anti-Infective Agents,
       Local/PHARMACOLOGY  Antiviral Agents/*ADMINISTRATION &
       DOSAGE/PHARMACOKINETICS  Chromatography, High Pressure Liquid
       Didanosine/ADMINISTRATION & DOSAGE/PHARMACOKINETICS
       Dideoxynucleosides/*ADMINISTRATION & DOSAGE/PHARMACOKINETICS  Enzyme
       Inhibitors/PHARMACOLOGY  Female  Half-Life  HIV-1/*DRUG EFFECTS  In
       Vitro  Rats  Rats, Nude  Skin Absorption/*DRUG EFFECTS  Support,
       Non-U.S. Gov't  Zalcitabine/ADMINISTRATION & DOSAGE/PHARMACOKINETICS
       Zidovudine/ADMINISTRATION & DOSAGE/PHARMACOKINETICS  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

