Tapentadol HCl is a centrally acting oral analgesic with a dual mechanism of action of μ-opioid agonist and norepinephrine reuptake inhibition. Serum pharmacokinetics of tapentadol were determined in healthy subjects after intravenous (IV) infusion of tapentadol HCl 10–80 mg (males, n=16) and 10–60 mg (females, n=8), and after oral, buccal, or IV administration of tapentadol HCl 60 mg (males, n=6). The excretion balance of radiocarbon was determined after administration of a single 100-mg oral dose of ¹⁴C-labeled tapentadol HCl (1.867 MBq, 50 μCi) to healthy males (n=4). All patients provided a written informed consent and study protocol were approved by the participating centers Institutional Review Boards. Following oral and IV administration of tapentadol HCl 60 mg, the AUC was 190±51 h·ng/mL and 588±46 h·ng/mL, respectively; C_max was 50.0±23.1 ng/mL and 299.5±48.7 ng/mL, respectively; T_max was 0.83±0.13 h and 0.18±0.03 h, respectively; and total clearance after IV administration was 1468±122 mL/min. After buccal administration, individual C_max values did not exceed 1.3 ng/mL. The absolute oral bioavailability was 31.9%±6.8%; buccal administration yielded no bioavailable tapentadol HCl. The pharmacokinetics of IV tapentadol HCl were linear; after body weight adjustment, no gender-specific differences were observed, except for a higher clearance rate in females at IV doses of 10 and 20 mg. Tapentadol was present in the serum primarily as conjugated glucuronide and sulfate metabolites (conjugated: unconjugated metabolites=24:1), and no active metabolites contributed to its analgesic activity. Tapentadol HCl was rapidly excreted in the urine (>95% of dose excreted within 24 h). Fecal excretion (1%) and expired CO₂ (negligible) accounted for the remainder. The most common adverse events associated with increasing doses of IV tapentadol HCl (10–80 mg) were sleepiness, vertigo, dry mouth, and nausea. Thus, tapentadol HCl was rapidly absorbed and excreted, and was well-tolerated.