Skin lipid synthesis inhibition: a possible means for enhancing percutaneous delivery of levodopa.
Skin perturbation with ethanol followed by application of beta-chloroalanine (beta-CA) or atorvastatin (AVN) was employed for delaying the recovery of sphingosine (a precursor of ceramide) and cholesterol, respectively in epidermis of rats. Dose optimization studies revealed 600 microg of beta-CA and 750 microg of AVN significantly (p<0.05) inhibited the synthesis of sphingosine and cholesterol, respectively and prevented their replenishment to normal levels till 48 hr in viable rat skin. Co-application of calcium chloride (0.1 mM) inhibited the synthesis of both micro constituents of epidermis to a greater magnitude, whereas verapamil reduced this effect. The in vitro permeation of levodopa across treated skin portions was directly correlated with percentage of sphingosine and cholesterol inhibited by the treatments. The in vitro permeation of levodopa across skin excised after treatment with beta-CA or AVN was enhanced 3-fold. Effective plasma concentration (1.58 microg/ml) of levodopa in rats was achieved within 2 hr and maintained till 12 hr after AVN treatment, and increased to 36 hr with the co-application of calcium chloride. However, when the skin was treated with beta-CA, Ceff was achieved after 4 hr and was maintained till 36 hr. The inclusion of calcium chloride maintained Ceff for 48 hr. Hence, synthesis inhibition of skin lipids seems to offer a feasible means to enhance the systemic delivery of polar drugs like levodopa.
Babita
Kumar
K
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147 002, India.
Tiwary
Ashok Kumar
AK
D000279:Administration, Cutaneous; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D000069059:Atorvastatin; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D002122:Calcium Chloride / Q000008:administration & dosage / Q000494:pharmacology; D002784:Cholesterol / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology; D066298:In Vitro Techniques; D007980:Levodopa / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D051102:Serine C-Palmitoyltransferase / Q000037:antagonists & inhibitors; D012867:Skin / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D013110:Sphingosine / Q000096:biosynthesis*; D013997:Time Factors; D014700:Verapamil / Q000008:administration & dosage / Q000494:pharmacology; D015091:beta-Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology
D000924:Anticholesteremic Agents; D000978:Antiparkinson Agents; D002121:Calcium Channel Blockers; D006538:Heptanoic Acids; D011758:Pyrroles; D015091:beta-Alanine; C006977:3-chloroalanine; D000431:Ethanol; D007980:Levodopa; D002784:Cholesterol; D000069059:Atorvastatin; D014700:Verapamil; D051102:Serine C-Palmitoyltransferase; D002122:Calcium Chloride; D013110:Sphingosine