Iontophoresis of endothelin receptor antagonists in rats and men.
BACKGROUND
The treatment of scleroderma-related digital ulcers is challenging. The oral endothelin receptor antagonist (ERA) bosentan has been approved but it may induce liver toxicity. The objective of this study was to test whether ERAs bosentan and sitaxentan could be locally delivered using iontophoresis.


METHODS
Cathodal and anodal iontophoresis of bosentan and sitaxentan were performed on anaesthetized rat hindquarters without and during endothelin-1 infusion. Skin blood flow was quantified using laser-Doppler imaging and cutaneous tolerability was assessed. Iontophoresis of sitaxentan (20 min, 20 or 100 µA) was subsequently performed on the forearm skin of healthy men (n = 5).


RESULTS
In rats neither bosentan nor sitaxentan increased skin blood flux compared to NaCl. When simultaneously infusing endothelin-1, cathodal iontophoresis of sitaxentan increased skin blood flux compared to NaCl (AUC(0-20) were 44032.2 ± 12277 and 14957.5 ± 23818.8 %BL.s, respectively; P = 0.01). In humans, sitaxentan did not significantly increase skin blood flux as compared to NaCl. Iontophoresis of ERAs was well tolerated both in animals and humans.


CONCLUSIONS
This study shows that cathodal iontophoresis of sitaxentan but not bosentan partially reverses endothelin-induced skin vasoconstriction in rats, suggesting that sitaxentan diffuses into the dermis. However, sitaxentan does not influence basal skin microvascular tone in rats or in humans.
Clinical Pharmacology Unit, Inserm CIC03, Grenoble University Hospital, Grenoble, France. MRoustit@chu-grenoble.fr
Matthieu
M
Roustit
Sophie
S
Blaise
Claire
C
Arnaud
Marcin
M
Hellmann
Claire
C
Millet
Diane
D
Godin-Ribuot
Boris
B
Dufournet
Jean
J
Boutonnat
Christophe
C
Ribuot
Jean-Luc
JL
Cracowski
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D004566:Electrodes; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007478:Iontophoresis / Q000379:methods*; D007555:Isoxazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D055815:Young Adult
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007555:Isoxazoles; D017466:Receptors, Endothelin; D013449:Sulfonamides; D013876:Thiophenes; C106276:sitaxsentan; D000077300:Bosentan