Decreased systemic clearance of lorazepam in humans with spinal cord injury.

Serum concentration-time course profiles, serum protein binding, and disposition parameters of lorazepam (LRZ), a benzodiazepine with sedative-hypnotic, anxiolytic, and anti-seizure properties, were studied as part of a systematic effort to define population-specific pharmacokinetic behavior in humans with chronic spinal cord injury (SCI). Twenty-four healthy subjects (nine tetraplegic, six paraplegic, nine able-bodied) were given an IV bolus of 2.0 mg of LRZ. Noncompartmental estimation of pharmacokinetic parameters disclosed a 37% decrease in the total systemic clearance (CL) of LRZ in tetraplegic patients. Altered LRZ clearance was observed independently of significant changes in volume of distribution or serum protein binding. The early elimination of LRZ (0-10 hr) was characterized by wide fluctuations in serum concentration suggestive of impaired enterohepatic circulation and could be distinguished from LRZ elimination observed in able-bodied subjects. We conclude that decreased systemic CL and the altered terminal elimination profile of LRZ are attributable to the pathophysiology of SCI.