The research team, led by anesthesiologists Che-Hao Hsu and Chih-Cherng Lu of Tungs’ Taichung MetroHarbor Hospital and Tri-Service General Hospital in Taiwan, set out to close a persistent gap in the anesthetic pharmacokinetic literature. Previous human studies had examined isoflurane uptake within the first 60 minutes after induction, but its elimination phase had been followed for only 20 minutes after surgery. That window is far too short to characterize the multi-compartmental terminal disposition kinetics that govern how anesthetics stored in fat and muscle eventually wash back out. Because the median duration of many common surgical procedures approximates two hours, and post-anesthesia care unit stays typically last less than two hours, the researchers chose a two-hour uptake phase followed by a two-hour disposition phase—a design that mirrors real clinical timelines while allowing the slow tissue kinetics to unfold.

Seven domestic five-month-old male piglets, weighing an average of 29.6 kilograms, received a fixed inspiratory concentration of 2 percent isoflurane—equivalent to the minimum alveolar concentration for piglets—delivered through a pre-washed circuit for two hours. The experiment then reversed course: the vaporizer was disconnected, and the animals breathed isoflurane-free gas for another two hours while the drug departed through the lungs. Throughout both phases, the team simultaneously measured inspiratory and end-tidal concentrations with an infrared analyzer, and drew one-milliliter samples of femoral arterial blood and pulmonary artery mixed venous blood at twelve time points, from 1 minute to 120 minutes. Isoflurane concentrations were determined by gas chromatography with a headspace sampler and flame ionization detector, a technique sensitive enough to track the drug down to vanishingly low levels.

The technical centerpiece of the study lies in how body uptake and disposition rates were calculated. By multiplying the difference between arterial and pulmonary artery blood concentrations by cardiac output—measured continuously with an Opti-Q catheter and thermodilution calibration—the researchers could quantify, moment by moment, how much isoflurane vapor the body was absorbing or releasing. Under Henry’s law, the amount of volatile agent vapor deriving from one milliliter of isoflurane fluid is 195 milliliters, allowing blood concentrations to be expressed as gas-equivalent vapor concentrations. Total body uptake and pulmonary disposition were then estimated from the area under the rate-time curves.

The results revealed a distinctive uptake profile. Rates of isoflurane body uptake increased gradually during the initial 20 minutes, reaching a peak of 20.7 milliliters per minute, before slowly declining to 10.5 milliliters per minute by 120 minutes. During the disposition phase, washout rates decreased continuously, falling from 6.3 milliliters per minute at 1 minute after cessation to 1.1 milliliters per minute at 120 minutes. The total body uptake over two hours was 7.5 milliliters of isoflurane fluid by blood and tissue, while the total amount eliminated over the subsequent two hours was just 1.1 milliliters—representing 14.5 percent of total uptake. Substantial amounts of the anesthetic, the authors conclude, likely remain in the body for hours after the vaporizer is turned off.

Pharmacokinetic modeling added a second layer of insight. The concentration-time curves for end-tidal, arterial blood, and pulmonary artery blood concentrations fit well with zero-order input and first-order disposition kinetics. In practical terms, this means that under a fixed inspired concentration, the body absorbed isoflurane at an approximately constant rate over the modeled 120-minute interval—empirically approximated by a zero-order input process—whereas the departure phase followed first-order kinetics, with the rate of elimination proportional to the concentration remaining in the body. Arterial and pulmonary artery blood concentrations were best modeled by a two-compartment system, selected on the basis of the Akaike information criterion and the principle of parsimony. A three-compartment model did not provide a statistically or practically significant improvement over the two-compartment model, so the simpler structure was retained.

The two-compartment framework aligns with what clinicians have long observed at the bedside. Emergence from general anesthesia with inhalational anesthetics is primarily driven by pulmonary exhalation and anesthetic disposition. Isoflurane is subject to little or no biotransformation—less than 0.2 percent—and percutaneous losses of only 0.35 percent of uptake, so kinetic studies need not account for metabolic elimination. While five-compartment models have been reported to fit washout curves up to five to nine days in healthy patients, the clinical reality of two-hour procedures and short recovery unit stays means that two distinct disposition components are what matter in practice: an initial rapid five-minute washout of functional residual capacity, followed by a slower constant diffusion of isoflurane from arterial blood to the alveolar space.

The study’s findings also quantitatively explain why isoflurane is associated with prolonged extubation times compared to sevoflurane and desflurane. The kinetics of wash-in and wash-out are governed by partition coefficients—critical indicators of how anesthetics distribute between blood and gas, and between tissues and blood. Isoflurane has a higher blood/gas partition coefficient than sevoflurane and desflurane in both pigs (0.94 versus 0.45 and 0.35) and humans (1.45 versus 0.74 and 0.57). Its fat/blood partition coefficient of 47.5 in humans reflects high tissue solubility, and theoretical calculations suggest that eliminating 99.9 percent of isoflurane from the brain can take up to 71 hours. In the current piglet study, the experimentally determined blood-gas partition coefficient before uptake was 0.97, and the average ratios of arterial over end-tidal concentrations ranged between 0.85 and 0.88 after five minutes during the uptake phase.

The pharmacokinetic parameters reported in the study extend previous human isoflurane research and the team’s earlier piglet desflurane model. Mean residence times differed markedly across the measured compartments: 7.4 minutes for end-tidal concentration, 15.1 minutes for arterial blood, and 28.6 minutes for pulmonary artery blood. Beta half-lives followed the same gradient, from 14.2 minutes at the end-tidal level to 45.3 minutes in pulmonary artery blood. These gradients capture the fundamental physiology of volatile anesthetic disposition—the drug departs the alveolar space quickly but lingers in the bloodstream and tissues far longer, creating the parallel but delayed concentration-time curves that the two-compartment model describes.

The authors emphasize that these fundamental pharmacokinetic parameters have practical implications for optimizing isoflurane delivery during induction, maintenance, and emergence in veterinary surgical practice, and they will facilitate future pharmacodynamic investigations into the drug’s cardioprotective effects. Isoflurane usage during cardiac surgery is beneficial for attenuation of myocardial damage, along with reduced intensive care unit and hospital length of stay, and a 2023 survey of cardiac anesthesiologists found that a majority selected isoflurane as the most frequently used primary agent for anesthesia maintenance across the prebypass, bypass, and postbypass periods. Most respondents—74 percent—believed isoflurane has organ-protective properties. By characterizing how the drug is absorbed at an approximately constant rate and how slowly it departs, the piglet study provides the quantitative foundation for understanding both the protective exposure window during surgery and the prolonged tissue retention that shapes recovery afterward. The limitations the authors note are candid: the 0.2 percent lower limit of detection accuracy for end-tidal isoflurane may limit measurement precision at low concentrations after 20 minutes of the disposition phase, and the two-hour uptake and two-hour disposition periods may be insufficient to fully characterize the multi-phase disposition kinetics of a drug with such high tissue solubility. Still, the agreement between predicted and experimental concentrations within the modeled two-hour window supports the two-compartment framework as a clinically relevant description of isoflurane disposition.

Subject of Research: Pharmacokinetics of isoflurane uptake and disposition in piglets

Article Title: Pharmacokinetics of isoflurane uptake and disposition in piglets

Article References: Hsu, C.-H., Lin, T.-C., Hu, O. Y.-P., Hsiong, C.-H., Ho, S.-T., & Lu, C.-C. (2026). Pharmacokinetics of isoflurane uptake and disposition in piglets. Frontiers in Pharmacology, 17, Article 1858313. https://doi.org/10.3389/fphar.2026.1858313

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1858313

Keywords: isoflurane, pharmacokinetics, anesthesia, piglets, uptake, disposition, scientific research