UHPLC–MS/MS Determination of Ramelteon in Rat Plasma and Its Altered Pharmacokinetics Under Simulated High Altitude: Relevance to High‐Altitude Sleep Disorders

High‐altitude hypoxia alters drug‐metabolizing enzymes, potentially affecting the pharmacokinetics of sedative‐hypnotics. Ramelteon, a melatonin receptor agonist for insomnia, is primarily eliminated via CYP1A2‐mediated first‐pass metabolism. A sensitive, ICH M10‐compliant UHPLC–MS/MS method was developed for ramelteon quantification in rat plasma using only 50 μL of sample and a 3.0‐min gradient elution on a CORTECS T3 column. The method was linear over 0.5–250.0 μg/L (LLOQ 0.5 μg/L, R 2 > 0.995). Intraday and interday accuracy and precision were within ± 15%, and matrix effects were consistent (IS‐normalized factor 89.5–95.7%, CV ≤ 7.8%). The method was applied to rats exposed to simulated high altitude (6500 m, 72 h). Compared with the local altitude group (1500 m), high‐altitude exposure significantly increased AUC 0–∞ (from 247.9 to 555.8 μg · h/L) and C max (from 214.0 to 693.2 μg/L), while oral clearance ( CL / F ) was reduced by more than half (from 21.6 to 9.5 L/h/kg). The terminal half‐life remained unchanged. Together with a proportional decrease in volume of distribution, these findings suggest that reduced first‐pass metabolism and altered distribution collectively lead to an unchanged half‐life. The elevated exposure indicates that a dose reduction may be warranted when ramelteon is used for high‐altitude sleep disorders.