In vivo pharmacological evaluation of a lactose-conjugated luteinizing hormone releasing hormone analogue.
In the current study, the efficacy and pharmacokinetic profile of lactose-conjugated luteinizing hormone releasing hormone (LHRH) was examined following oral administration in male rats. A rapid and sensitive liquid chromatography/mass spectrometry technique was developed and applied for measuring the concentration of lactose[Q(1)][w(6)]LHRH (compound 1) in rat plasma in order to allow measurement of pharmacokinetic parameters. LH release was evaluated using a sandwich ELISA. Maximum serum concentration (Cmax = 0.11 μg/ml) was reached at 2h (Tmax) following oral administration of the compound at 10mg/kg. The half-life was determined to be 2.6h. The absolute bioavailability of the orally administered compound was found to be 14%, which was a remarkable improvement compared to zero-to-low oral bioavailability of the native peptide. Compound 1 was effective in stimulating LH release at 20mg/kg after oral administration. The method was validated at a linear range of 0.01-20.0 μg/ml and a correlation coefficient of r(2) ≥ 0.999. The accuracy and precision values showed the reliability and reproducibility of the method for evaluation of the pharmacokinetic parameters. These findings showed that the lactose derivative of LHRH has a therapeutic potential to be further developed as an orally active therapeutics for the treatment of hormone-dependent diseases.
School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland 4072, Australia.
Shayli
S
Varasteh Moradi
School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland 4072, Australia.
Pegah
P
Varamini
The University of Queensland Centre for Clinical Research and the School of Biomedical Sciences, The University of Queensland, St. Lucia, Queensland 4072, Australia.
Frederik
F
Steyn
School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland 4072, Australia; School of Pharmacy, The University of Queensland, Woolloongabba, Queensland 4102, Australia.
Istvan
I
Toth
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D007785:Lactose / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051381:Rats
D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D007785:Lactose
Bioavailability; LC/MS; LH release; LHRH; Pharmacokinetic