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
Medical Research Council Toxicology Unit, University of Leicester, PO Box 138, Leicester, LE1 9HN, UK.
Br J Cancer. 2000 Oct;83(7):935-40. doi: 10.1054/bjoc.2000.1421.
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.
长期反复口服化学预防类视黄醇（如异维甲酸）会产生难以耐受的全身毒性。在此，异维甲酸被制成粉末气雾剂，并对其在大鼠肺部的递送情况进行了研究，目的是探索将口服给药相关不良反应降至最低的可能性。大鼠通过口服（0.5、1或10 mg kg⁻¹）或在仅用于鼻腔吸入的舱室中吸入（理论剂量约为1或约10 mg kg⁻¹）接受异维甲酸。通过高压液相色谱法对血浆和肺组织中的异维甲酸进行定量。单次或重复气雾剂暴露后，肺部浓度-时间曲线平均面积（AUC）值与血浆中AUC值的比值超过口服途径所测比值，倍数在2（单次低剂量）至5（单次高剂量）之间。同样，气雾剂暴露后肺部和血浆中最大峰值浓度的等效比值始终超过口服给药后的比值，这表明气雾剂吸入后肺部暴露于更高的异维甲酸浓度，高于相似剂量口服给药后的浓度。重复高剂量吸入异维甲酸导致体重适度减轻，但对包括肺和食管在内的10个组织进行显微镜检查未发现任何明显的气雾剂诱导损伤。结果表明，就肺部达到有效药物浓度而言，通过粉末气雾剂吸入给予异维甲酸可能优于口服给药。
