Pharmacokinetics and pharmacodynamics of mivacurium stereoisomers in beagle dogs using twitch height and train-of-four response.

Mivacurium, a non-depolarizing neuromuscular blocking agent, consists of three isomers; trans-trans (57%), cis-trans (36%) and cis-cis (7%). The purpose of this study was to characterize the pharmacokinetics and pharmacodynamics of mivacurium after various inputs. Four beagle dogs weighing between 7.95 and 9.89 kg were anesthetized with isofluorane (5%) and received a bolus dose (0.010-0.020 mg kg(-1)) and two constant rate infusions (1.0-1.5 microg kg(-1) min(-1)) of mivacurium via the saphenous vein. Single twitch height (TH) and train-of-four (TOF) were evaluated every 15 and 30 s, respectively. Arterial blood samples were collected, processed and analysed for mivacurium using a stereospecific HPLC-fluorescence method. The disposition of mivacurium isomers was best described by a two compartment model. Mean Cl for the cis-trans, trans-trans and cis-cis isomers were 19.98, 13.53 and 3.47 mL min(-1) kg(-1) respectively and the corresponding mean Vdss were 0.29, 0.24 and 1.00 L kg(-1). The measurement of onset showed dose dependence as evidenced by a rapid onset at the higher doses. TOF measurements were more sensitive to the onset of action and required a longer period of time to recover to baseline values as compared with TH measurements.

Rapid method for the quantitation of mivacurium isomers in human and dog plasma by using liquid chromatography with fluorescence detection: application to pharmacokinetic studies.

A simple, selective and specific liquid chromatography method was used to simultaneously determine the cis-cis, cis-trans and trans-trans isomers of mivacurium in human and dog plasma. Solid phase extraction was used to separate interfering endogenous products from the compounds of interest. Fluorometric detection was evaluated at excitation and emission maxima of 280 and 325 nm. The calibration curves were found to be linear in the range 50-500 ng ml-1. The method was applied to plasma samples collected from a human and dog study and was found to be satisfactory. Excellent recovery, linearity, accuracy and precision were achieved by the assay for each isomer.

Dose-dependent caffeine pharmacokinetics during severe sleep deprivation in humans.

Following 49 h of sleep deprivation, 37 healthy males ingested either 2.1, 4.3, or 8.6 mg*kg-1 body weight of caffeine in a randomized double-blind design. Subjects were sleep deprived for additional 12 h and venous blood samples were collected intermittently. Caffeine and primary metabolite concentrations were determined by HPLC. Pharmacokinetics were computed using the Lagran computer program. The ratio of the primary human metabolite, paraxanthine, to caffeine was used to estimate the rate of metabolism. There was a significant (p < 0.05) and disproportional increase in the dose normalized caffeine AUC and a significant decrease in its clearance associated with increasing dose. In addition, the paraxanthine to caffeine ratio significantly decreased with an increase in dose, indicating that the rate of caffeine metabolism decreased. These results demonstrate that under the conditions of severe sleep deprivation caffeine exhibits dose-dependent pharmacokinetics. In addition, these results are consistent with a model of capacity-limited metabolism.