Abstract
HsTX1[R14A] is a potent and selective Kv1.3 channel blocker peptide with the potential to treat autoimmune diseases. Given the typically poor oral bioavailability of peptides, we evaluated pulmonary administration of HsTX1[R14A] in rats as an alternative route for systemic delivery. Plasma concentrations of HsTX1[R14A] were measured by liquid chromatography coupled with tandem mass spectrometry in rats receiving intratracheal administration of HsTX1[R14A] in solution (1-4 mg/kg) or a mannitol-based powder (1 mg/kg) and compared with plasma concentrations after intravenous administration (2 mg/kg). HsTX1[R14A] stability in rat plasma and lung tissue was also determined. HsTX1[R14A] was more stable in plasma than in lung homogenate, with more than 90% of the HsTX1[R14A] remaining intact after 5 h, compared with 40.5% remaining in lung homogenate. The terminal elimination half-life, total clearance, and volume of distribution of HsTX1[R14A] after intravenous administration were 79.6 ± 6.5 min, 8.3 ± 0.6 mL/min/kg, and 949.8 ± 71.0 mL/kg, respectively (mean ± SD). After intratracheal administration, HsTX1[R14A] in solution and dry powder was absorbed to a similar degree, with absolute bioavailability values of 39.2 ± 5.2% and 44.5 ± 12.5%, respectively. This study demonstrated that pulmonary administration is a promising alternative for systemically delivering HsTX1[R14A] for treating autoimmune diseases.
| Original language | English |
|---|---|
| Pages (from-to) | 650-656 |
| Number of pages | 7 |
| Journal | Journal of Pharmaceutical Sciences |
| Volume | 105 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 1 Feb 2016 |
Keywords
- epithelial delivery
- peptides
- pharmacokinetics
- pulmonary absorption
- pulmonary drug delivery
Cite this
}
Pulmonary delivery of the Kv1.3-blocking peptide HsTX1[R14A] for the treatment of autoimmune diseases. / Jin, Liang; Zhou, Qi (Tony); Chan, Hak-Kim; Larson, Ian C.; Pennington, Michael W.; Morales, Rodrigo A.V.; Boyd, Ben J.; Norton, Raymond S.; Nicolazzo, Joseph A.
In: Journal of Pharmaceutical Sciences, Vol. 105, No. 2, 01.02.2016, p. 650-656.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Pulmonary delivery of the Kv1.3-blocking peptide HsTX1[R14A] for the treatment of autoimmune diseases
AU - Jin, Liang
AU - Zhou, Qi (Tony)
AU - Chan, Hak-Kim
AU - Larson, Ian C.
AU - Pennington, Michael W.
AU - Morales, Rodrigo A.V.
AU - Boyd, Ben J.
AU - Norton, Raymond S.
AU - Nicolazzo, Joseph A.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - HsTX1[R14A] is a potent and selective Kv1.3 channel blocker peptide with the potential to treat autoimmune diseases. Given the typically poor oral bioavailability of peptides, we evaluated pulmonary administration of HsTX1[R14A] in rats as an alternative route for systemic delivery. Plasma concentrations of HsTX1[R14A] were measured by liquid chromatography coupled with tandem mass spectrometry in rats receiving intratracheal administration of HsTX1[R14A] in solution (1-4 mg/kg) or a mannitol-based powder (1 mg/kg) and compared with plasma concentrations after intravenous administration (2 mg/kg). HsTX1[R14A] stability in rat plasma and lung tissue was also determined. HsTX1[R14A] was more stable in plasma than in lung homogenate, with more than 90% of the HsTX1[R14A] remaining intact after 5 h, compared with 40.5% remaining in lung homogenate. The terminal elimination half-life, total clearance, and volume of distribution of HsTX1[R14A] after intravenous administration were 79.6 ± 6.5 min, 8.3 ± 0.6 mL/min/kg, and 949.8 ± 71.0 mL/kg, respectively (mean ± SD). After intratracheal administration, HsTX1[R14A] in solution and dry powder was absorbed to a similar degree, with absolute bioavailability values of 39.2 ± 5.2% and 44.5 ± 12.5%, respectively. This study demonstrated that pulmonary administration is a promising alternative for systemically delivering HsTX1[R14A] for treating autoimmune diseases.
AB - HsTX1[R14A] is a potent and selective Kv1.3 channel blocker peptide with the potential to treat autoimmune diseases. Given the typically poor oral bioavailability of peptides, we evaluated pulmonary administration of HsTX1[R14A] in rats as an alternative route for systemic delivery. Plasma concentrations of HsTX1[R14A] were measured by liquid chromatography coupled with tandem mass spectrometry in rats receiving intratracheal administration of HsTX1[R14A] in solution (1-4 mg/kg) or a mannitol-based powder (1 mg/kg) and compared with plasma concentrations after intravenous administration (2 mg/kg). HsTX1[R14A] stability in rat plasma and lung tissue was also determined. HsTX1[R14A] was more stable in plasma than in lung homogenate, with more than 90% of the HsTX1[R14A] remaining intact after 5 h, compared with 40.5% remaining in lung homogenate. The terminal elimination half-life, total clearance, and volume of distribution of HsTX1[R14A] after intravenous administration were 79.6 ± 6.5 min, 8.3 ± 0.6 mL/min/kg, and 949.8 ± 71.0 mL/kg, respectively (mean ± SD). After intratracheal administration, HsTX1[R14A] in solution and dry powder was absorbed to a similar degree, with absolute bioavailability values of 39.2 ± 5.2% and 44.5 ± 12.5%, respectively. This study demonstrated that pulmonary administration is a promising alternative for systemically delivering HsTX1[R14A] for treating autoimmune diseases.
KW - epithelial delivery
KW - peptides
KW - pharmacokinetics
KW - pulmonary absorption
KW - pulmonary drug delivery
UR - http://www.scopus.com/inward/record.url?scp=84964465697&partnerID=8YFLogxK
U2 - 10.1016/j.xphs.2015.10.025
DO - 10.1016/j.xphs.2015.10.025
M3 - Article
VL - 105
SP - 650
EP - 656
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
SN - 0022-3549
IS - 2
ER -