Population Pharmacokinetics of Amitriptyline After Intrathecal, Epidural, and Intravenous Administration in Sheep.

BACKGROUND: Amitriptyline (AMI) is a lipophilic, tricyclic antidepressant with analgesic properties that could potentially be used for epidural (EPI) analgesia. However, no pharmacokinetic data are available for AMI in spinal spaces. The objective of this study was to evaluate the spinal disposition and intrathecal (IT) bioavailability of AMI after IT and EPI administration. METHODS: Six Lacaune ewes received 3 consecutive administrations of AMI. They initially received 10 mg of AMI administered intravenously, then 5 mg of AMI administered intrathecally, and 50 mg of AMI injected into the EPI space. Consecutive administrations were separated by intervals of 2 hours. A simultaneous microdialysis technique was used to determine the EPI and IT concentrations of AMI. Population analysis with S-ADAPT software was used to evaluate the pharmacokinetic parameters. RESULTS: Following intravenous administration, the clearance and central compartment (Vc) in plasma were 1.32 L/min and 147 L, respectively. Concentration-time profiles for the IT and EPI compartments were highly variable after transmeningeal diffusion. The IT Vc after IT administration and the EPI Vc after EPI administration were 2.4 and 48.9 mL, respectively. Less AMI transferred from the EPI to the IT space than from the IT to the EPI compartment, with bioavailabilities of 1.3% and 55%, respectively. CONCLUSIONS: Simultaneous population analysis for AMI demonstrated differences in EPI and IT pharmacokinetics following the EPI and IT administration of this drug. The IT bioavailability of AMI after EPI administration is relatively low.

Electrocardiographic and hemodynamic effects of intravenous infusion of bupivacaine, ropivacaine, levobupivacaine, and lidocaine in anesthetized ewes.

BACKGROUND AND OBJECTIVES: Neural blockade techniques are associated with a risk of acute cardiac toxicity after accidental intravenous (IV) injection of local anesthetics. The aim of this study was to compare electrocardiographic (ECG) and hemodynamic (HEM) effects induced by IV infusion of local anesthetics in an anesthetized ewe model. METHODS: Thirty-two anesthetized ewes received IV bupivacaine (BUPI), ropivacaine (ROPI), or levobupivacaine (S-BUPI) at an equimolar dose, or lidocaine (LIDO) at a 3-fold higher rate (n = 8 in each group). RR, PR, QRS, and QT intervals (QTc), changes (Delta) in systolic and diastolic arterial pressure (SAP and DAP), and in myocardial contractility (dP/dt), were assessed every 30 seconds for 7 minutes. From main ECG variables (RR, PR, QRS, QT), we proposed to use multiple correspondence analysis and hierarchical ascending classification to explore the structure of statistical dependencies among those measurements, and to determine the different patterns of ECG and HEM changes induced by infusion of BUPI, ROPI, S-BUPI, and LIDO. RESULTS: Graphic representation of multiple correspondence analysis associated BUPI with the most pronounced modifications in ECG and HEM variables, followed by in decreasing order ROPI, S-BUPI, and LIDO. Comparisons of clusters identified by hierarchical ascending classification confirmed this classification for ECG variables. Ventricular tachycardia occurred only in the BUPI group. CONCLUSIONS: In our anesthetized ewe model, high dose IV infusion of BUPI induced the most marked changes in RR, PR, QRS, QT, QTc intervals, DeltaSAP, and DeltadP/dt. ROPI altered ECG variables less than BUPI but more than S-BUPI. LIDO was associated with the smallest changes.

Epidural, intrathecal and plasma pharmacokinetic study of epidural ropivacaine in PLGA-microspheres in sheep model.

BACKGROUND: Microparticulate local anesthetics-loaded delivery systems are known to provide a controlled release of drug and to reduce systemic toxicity resulting from transient high plasma concentrations. The aim of this study was to evaluate epidural, intrathecal and plasma pharmacokinetics of ropivacaine following epidural administrations of repeated boluses or infusions and to compare them with the epidural administration of polylactide-co-glycolide ropivacaine-loaded microspheres. METHODS: In the first step, the epidural and intrathecal pharmacokinetics was evaluated in 3 Lacaunes ewes, receiving epidural continuous infusion of ropivacaine with increasing doses (20, 50 and 100mg/h). Then, six animals received an epidural administration of ropivacaine-loaded microspheres (500 mg), three others received ropivacaine in epidural bolus (30 mg) followed by infusion (2mg/ml during 6h), and the last three animals received three successive epidural boluses of ropivacaine (50mg) at 2h interval. A simultaneous microdialysis technique was used to measure epidural and intrathecal concentrations of ropivacaine. RESULTS: After epidural administration of ropivacaine-loaded microspheres, Cmax in plasma was around 100 ng/ml while epidural and intrathecal Cmax of ropivacaine were close to 600 and 150 microg/ml, respectively. The ratios of intrathecal to epidural AUC (AUCit/AUCepi) for bolus administration, bolus+infusion administration, and for microspheres were 13.4+/-2.4; 14.1+/-6.1 and 33.9+/-22.6%, respectively. This suggested that administration of ropivacaine as microspheres increased the transmeningeal passage of ropivacaine in comparison to other administration regimens. CONCLUSIONS: Epidural administration of ropivacaine-loaded microspheres led to the sustained levels of ropivacaine in the intrathecal space compared to the boluses of ropivacaine solution. Moreover, epidural administration of microspheres resulted in the highest efficiency in intrathecal uptake of ropivacaine compared to administration in solution.

Epidural, intrathecal pharmacokinetics, and intrathecal bioavailability of ropivacaine.

BACKGROUND: Ropivacaine is used by the epidural route for postoperative pain management with various neuraxial techniques. Given the widespread use of these techniques and the relative paucity of data on spinal disposition of local anesthetics, we evaluated through an experimental animal model, the spinal disposition of ropivacaine, allowing further studies of factors influencing their intrathecal bioavailability. METHODS: Sheep received an IV bolus dose of ropivacaine (50 mg), and 1 wk after, an intrathecal dose of ropivacaine (20 mg) followed 3 h later by epidural ropivacaine (100 mg). A simultaneous microdialysis technique was used to measure epidural and intrathecal drug concentrations after both epidural and intrathecal administrations. RESULTS: Absorption-time plots showed a large variability in the systemic absorption after both intrathecal and epidural administration, with an apparent faster systemic absorption after intrathecal administration. In the intrathecal space, the elimination clearance was around three-times higher than the distribution clearance. In the epidural space, the relative contribution of elimination and distribution to ropivacaine disposition was different, indicating a more pronounced influence of the distribution process. The intrathecal bioavailability after epidural administration was 11.1% +/- 7.6%. CONCLUSIONS: Using an animal model, we showed that drug dispositions in the intrathecal and epidural compartments are different, and that the intrathecal bioavailability of ropivacaine after epidural administration is low, and highly variable.