Pulmonary availability of isotretinoin in rats after inhalation of a powder aerosol

S M Raleigh, R D Verschoyle, C Bowskill, U Pastorino, J N Staniforth, F Steele, D Dinsdale, P Carthew, C K Lim, J Silvester, A Gescher

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Repeated oral administration of chemopreventive retinoids such as isotretinoin over extended periods of time is associated with intolerable systemic toxicity. Here isotretinoin was formulated as a powder aerosol, and its delivery to the lungs of rats was studied with the aim to explore the possibility of minimizing adverse effects associated with its oral administration. Rats received isotretinoin orally (0.5, 1 or 10 mg kg(-1)) or by inhalation (theoretical dose approximately 1 or approximately 10 mg kg(-1)) in a nose-only inhalation chamber. Isotretinoin was quantitated by high-pressure liquid chromatography in plasma and lung tissue. The ratios of mean area of concentration-vs-time curve (AUC) values in the lungs over mean AUCs in the plasma for isotretinoin following single or repeated aerosol exposure surpassed those determined for the oral route by factors of between two (single low-dose) and five (single high-dose). Similarly, the equivalent ratios for the maximal peak concentrations in lungs and plasma obtained after aerosol exposure consistently exceeded those seen after oral administration, suggesting that lungs were exposed to higher isotretinoin concentrations after aerosol inhalation than after oral administration of similar doses. Repeated high doses of isotretinoin by inhalation resulted in moderate loss of body weight, but microscopic investigation of ten tissues including lung and oesophagus did not detect any significant aerosol-induced damage. The results suggest that administration of isotretinoin via powder aerosol inhalation is probably superior to its application via the oral route in terms of achieving efficacious drug concentrations in the lungs.

Original languageEnglish
Pages (from-to)935-940
Number of pages6
JournalBritish Journal of Cancer
Volume83
Issue number7
DOIs
Publication statusPublished - Oct 2000
Externally publishedYes

Fingerprint

Isotretinoin
Aerosols
Powders
Inhalation
Lung
Oral Administration
Area Under Curve
Retinoids
Nose
Esophagus
High Pressure Liquid Chromatography
Body Weight

Keywords

  • Administration, Inhalation
  • Administration, Oral
  • Aerosols
  • Animals
  • Anticarcinogenic Agents
  • Biological Availability
  • Dose-Response Relationship, Drug
  • Female
  • Isotretinoin
  • Lung
  • Rats
  • Rats, Inbred F344
  • Comparative Study
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Raleigh, S. M., Verschoyle, R. D., Bowskill, C., Pastorino, U., Staniforth, J. N., Steele, F., ... Gescher, A. (2000). Pulmonary availability of isotretinoin in rats after inhalation of a powder aerosol. British Journal of Cancer, 83(7), 935-940. https://doi.org/10.1054/bjoc.2000.1421

Pulmonary availability of isotretinoin in rats after inhalation of a powder aerosol. / Raleigh, S M; Verschoyle, R D; Bowskill, C; Pastorino, U; Staniforth, J N; Steele, F; Dinsdale, D; Carthew, P; Lim, C K; Silvester, J; Gescher, A.

In: British Journal of Cancer, Vol. 83, No. 7, 10.2000, p. 935-940.

Research output: Contribution to journalArticle

Raleigh, SM, Verschoyle, RD, Bowskill, C, Pastorino, U, Staniforth, JN, Steele, F, Dinsdale, D, Carthew, P, Lim, CK, Silvester, J & Gescher, A 2000, 'Pulmonary availability of isotretinoin in rats after inhalation of a powder aerosol' British Journal of Cancer, vol. 83, no. 7, pp. 935-940. https://doi.org/10.1054/bjoc.2000.1421
Raleigh, S M ; Verschoyle, R D ; Bowskill, C ; Pastorino, U ; Staniforth, J N ; Steele, F ; Dinsdale, D ; Carthew, P ; Lim, C K ; Silvester, J ; Gescher, A. / Pulmonary availability of isotretinoin in rats after inhalation of a powder aerosol. In: British Journal of Cancer. 2000 ; Vol. 83, No. 7. pp. 935-940.
@article{beda1057ec5c4a16a0f3c4e33034519d,
title = "Pulmonary availability of isotretinoin in rats after inhalation of a powder aerosol",
abstract = "Repeated oral administration of chemopreventive retinoids such as isotretinoin over extended periods of time is associated with intolerable systemic toxicity. Here isotretinoin was formulated as a powder aerosol, and its delivery to the lungs of rats was studied with the aim to explore the possibility of minimizing adverse effects associated with its oral administration. Rats received isotretinoin orally (0.5, 1 or 10 mg kg(-1)) or by inhalation (theoretical dose approximately 1 or approximately 10 mg kg(-1)) in a nose-only inhalation chamber. Isotretinoin was quantitated by high-pressure liquid chromatography in plasma and lung tissue. The ratios of mean area of concentration-vs-time curve (AUC) values in the lungs over mean AUCs in the plasma for isotretinoin following single or repeated aerosol exposure surpassed those determined for the oral route by factors of between two (single low-dose) and five (single high-dose). Similarly, the equivalent ratios for the maximal peak concentrations in lungs and plasma obtained after aerosol exposure consistently exceeded those seen after oral administration, suggesting that lungs were exposed to higher isotretinoin concentrations after aerosol inhalation than after oral administration of similar doses. Repeated high doses of isotretinoin by inhalation resulted in moderate loss of body weight, but microscopic investigation of ten tissues including lung and oesophagus did not detect any significant aerosol-induced damage. The results suggest that administration of isotretinoin via powder aerosol inhalation is probably superior to its application via the oral route in terms of achieving efficacious drug concentrations in the lungs.",
keywords = "Administration, Inhalation, Administration, Oral, Aerosols, Animals, Anticarcinogenic Agents, Biological Availability, Dose-Response Relationship, Drug, Female, Isotretinoin, Lung, Rats, Rats, Inbred F344, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't",
author = "Raleigh, {S M} and Verschoyle, {R D} and C Bowskill and U Pastorino and Staniforth, {J N} and F Steele and D Dinsdale and P Carthew and Lim, {C K} and J Silvester and A Gescher",
note = "Copyright 2000 Cancer Research Campaign.",
year = "2000",
month = "10",
doi = "10.1054/bjoc.2000.1421",
language = "English",
volume = "83",
pages = "935--940",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Cancer Research UK",
number = "7",

}

TY - JOUR

T1 - Pulmonary availability of isotretinoin in rats after inhalation of a powder aerosol

AU - Raleigh, S M

AU - Verschoyle, R D

AU - Bowskill, C

AU - Pastorino, U

AU - Staniforth, J N

AU - Steele, F

AU - Dinsdale, D

AU - Carthew, P

AU - Lim, C K

AU - Silvester, J

AU - Gescher, A

N1 - Copyright 2000 Cancer Research Campaign.

PY - 2000/10

Y1 - 2000/10

N2 - Repeated oral administration of chemopreventive retinoids such as isotretinoin over extended periods of time is associated with intolerable systemic toxicity. Here isotretinoin was formulated as a powder aerosol, and its delivery to the lungs of rats was studied with the aim to explore the possibility of minimizing adverse effects associated with its oral administration. Rats received isotretinoin orally (0.5, 1 or 10 mg kg(-1)) or by inhalation (theoretical dose approximately 1 or approximately 10 mg kg(-1)) in a nose-only inhalation chamber. Isotretinoin was quantitated by high-pressure liquid chromatography in plasma and lung tissue. The ratios of mean area of concentration-vs-time curve (AUC) values in the lungs over mean AUCs in the plasma for isotretinoin following single or repeated aerosol exposure surpassed those determined for the oral route by factors of between two (single low-dose) and five (single high-dose). Similarly, the equivalent ratios for the maximal peak concentrations in lungs and plasma obtained after aerosol exposure consistently exceeded those seen after oral administration, suggesting that lungs were exposed to higher isotretinoin concentrations after aerosol inhalation than after oral administration of similar doses. Repeated high doses of isotretinoin by inhalation resulted in moderate loss of body weight, but microscopic investigation of ten tissues including lung and oesophagus did not detect any significant aerosol-induced damage. The results suggest that administration of isotretinoin via powder aerosol inhalation is probably superior to its application via the oral route in terms of achieving efficacious drug concentrations in the lungs.

AB - Repeated oral administration of chemopreventive retinoids such as isotretinoin over extended periods of time is associated with intolerable systemic toxicity. Here isotretinoin was formulated as a powder aerosol, and its delivery to the lungs of rats was studied with the aim to explore the possibility of minimizing adverse effects associated with its oral administration. Rats received isotretinoin orally (0.5, 1 or 10 mg kg(-1)) or by inhalation (theoretical dose approximately 1 or approximately 10 mg kg(-1)) in a nose-only inhalation chamber. Isotretinoin was quantitated by high-pressure liquid chromatography in plasma and lung tissue. The ratios of mean area of concentration-vs-time curve (AUC) values in the lungs over mean AUCs in the plasma for isotretinoin following single or repeated aerosol exposure surpassed those determined for the oral route by factors of between two (single low-dose) and five (single high-dose). Similarly, the equivalent ratios for the maximal peak concentrations in lungs and plasma obtained after aerosol exposure consistently exceeded those seen after oral administration, suggesting that lungs were exposed to higher isotretinoin concentrations after aerosol inhalation than after oral administration of similar doses. Repeated high doses of isotretinoin by inhalation resulted in moderate loss of body weight, but microscopic investigation of ten tissues including lung and oesophagus did not detect any significant aerosol-induced damage. The results suggest that administration of isotretinoin via powder aerosol inhalation is probably superior to its application via the oral route in terms of achieving efficacious drug concentrations in the lungs.

KW - Administration, Inhalation

KW - Administration, Oral

KW - Aerosols

KW - Animals

KW - Anticarcinogenic Agents

KW - Biological Availability

KW - Dose-Response Relationship, Drug

KW - Female

KW - Isotretinoin

KW - Lung

KW - Rats

KW - Rats, Inbred F344

KW - Comparative Study

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1054/bjoc.2000.1421

DO - 10.1054/bjoc.2000.1421

M3 - Article

VL - 83

SP - 935

EP - 940

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 7

ER -