Metabolism and Pharmacokinetics

Dexmedetomidine is rapidly distributed and extensively metabolized in the liver and excreted in both urine and feces. It undergoes conjugation (41%), N-methylation (21%), or hydroxylation followed by conjugation. Dexmedetomidine is 94% protein bound, and its concentration ratio between whole blood and plasma is 0.66. Dexmedetomidine has profound effects on cardiovascular parameters and thus may alter its own pharmacokinetics. At high doses it causes marked vasoconstriction, which probably reduces the drug's volumes of distribution. Thus, in essence, dexmedetomidine displays nonlinear pharmacokinetics.^[19] Because it is likely that this drug will be administered only within a narrow therapeutic range of 0.5 to 1.0 ng/mL, it is preferable to describe the pharmacokinetic parameters within this dosage range. Within this range, Dyck and colleagues^[19] found that its pharmacokinetics in volunteers is best described by a three-compartment model (see Table 10-1 ). These pharmacokinetic parameters appear to be unaltered by age, weight, or renal failure, but clearance is a function of height.^{[19] [663]} The elimination half-life of dexmedetomidine is 2 to 3 hours, with a context sensitive half-time ranging from 4 minutes after a 10-minute infusion to 250 minutes after an 8-hour infusion. Postoperative patients sedated with dexmedetomidine display pharmacokinetics very similar to that seen in volunteers.^[20]