Conjunctival penetration of insulin and peptide drugs in the albino rabbit.
An in vitro model was used to evaluate the conjunctival penetration of three peptides, [D-ala2]metenkephalinamide (YAGFM, MW 647), substance P (MW 1348), and insulin (MW 5778), in comparison with two nonpeptides, atenolol (MW 266) and timolol (MW 433). All three peptides were hydrolyzed to varying extents during penetration across the conjunctiva. The permeability coefficient for intact YAGFM and insulin was 4.5 +/- 0.3 and 4.6 +/- 0.7 microns sec-1, respectively. These values were about two to five times lower than those for atenolol and timolol. No permeability coefficient could be calculated for substance P, since its transconjunctival flux never reached steady state. The conjunctival penetration of YAGFM and insulin was improved by about two and three times, respectively, with the addition of 1% Na glycocholate. Increasing the Na glycocholate concentration was more effective than changing the type of bile salt in improving the conjunctival penetration of insulin. The maximum factor of improvement was 12, as the Na glycocholate concentration was raised to 4%. The way in which Na deoxycholate, glycocholate, and taurocholate affected the conjunctival penetration of atenolol, timolol, and insulin suggests that these three bile salts improved mainly the transcellular penetration of the compounds studied.
Hayakawa
E
E
University of Southern California, School of Pharmacy, Department of Pharmaceutical Sciences, Los Angeles 90033.
Chien
D S
DS
Inagaki
K
K
Yamamoto
A
A
Wang
W
W
Lee
V H
VH
D000287:Administration, Topical; D000818:Animals; D001262:Atenolol / Q000008:administration & dosage / Q000493:pharmacokinetics; D001647:Bile Acids and Salts / Q000494:pharmacology; D003228:Conjunctiva / Q000378:metabolism*; D004744:Enkephalin, Methionine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006000:Glycocholic Acid / Q000494:pharmacology; D007328:Insulin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008970:Molecular Weight; D009883:Ophthalmic Solutions; D011817:Rabbits; D013373:Substance P / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013999:Timolol / Q000008:administration & dosage / Q000493:pharmacokinetics
D001647:Bile Acids and Salts; D007328:Insulin; D009883:Ophthalmic Solutions; D013373:Substance P; D001262:Atenolol; D004744:Enkephalin, Methionine; C022118:enkephalinamide-Met, Ala(2)-; D013999:Timolol; D006000:Glycocholic Acid