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Fampridine SR (4-aminopyridine) is a potassium channel-blocking drug currently being investigated for its therapeutic efficacy in ameliorating central conduction deficits due to demyelination in patients with spinal cord injury (SCI). The present open-label pharmacokinetic trial examined the absorption characteristics of a sustained-release form of the drug in 25 SCI subjects with chronic incomplete injuries. The overall group mean Cmax of 27.7 +/- 6.2 ng/mL occurred at a tmax of 3.4 +/- 1.4 hours. AUC0-12 was 210.5 +/- 49.5 ng/mL.h. For paraplegics, AUCtmax was 76.02 +/- 33.28 and for tetraplegics was significantly less at 51.25 +/- 20.36 (p = 0.037). A statistically significant difference in the initial rate and extent of absorption, but not in total 4-AP bioavailability over the 12-hour study period, was evident between tetraplegic patients, 0.60 +/- 0.23, and paraplegic patients, 0.39 +/- 0.14 (p = 0.02). There was a linear correlation (p < 0.05) between the neurological level of injury and Cmax/AUCtmax. These results confirm and extend previous observations of different rates of drug absorption among SCI patients with lesions above and below the sympathetic outflow (T6) and provide evidence of the absorption characteristics of this sustained-release form of 4-aminopyridine, which is helpful for optimal dosing.

A study was conducted to determine the effect of metoclopramide on the disposition of dantrolene in patients with spinal cord injury (SCI) and in neurologically intact, able-bodied volunteers. Fifteen serum samples each were collected from 6 able-bodied volunteers and 13 patients with SCI (7 paraplegics, 6 quadriplegics) in a prospective, open-label, pharmacokinetic study of a single 100-mg oral dose of dantrolene. After a washout period, a single 10-mg intravenous dose of metoclopramide was given along with dantrolene to the patients with SCI only, and the study was repeated in sequential, crossover fashion. Concentrations of dantrolene were measured by a high-performance liquid chromatography (HPLC) assay. Numerical integration was used to calculate area under the curve (AUC) and mean residence time (MRT). Differences were studied using paired and two-sample, nonparametric tests, with 0.05 as the significance level. Without metoclopramide, the AUC of dantrolene was larger in able-bodied volunteers than in patients with SCI, and the MRT of dantrolene was similar both groups. When patients with SCI received metoclopramide before treatment with dantrolene, the median increase in the AUC for dantrolene was 57%, with no change in MRT. This pharmacokinetic interaction is probably attributable to augmented absorption and could alter the pharmacologic action of dantrolene. Concurrent treatment of patients with SCI with metoclopramide and dantrolene should be accompanied by careful surveillance to avoid toxicity and preserve efficacy.

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.