It is known that acute spinal cord injury (SCI) produces hemodynamic alterations, including a reduction in liver blood flow that is more pronounced after high-thoracic than after low-thoracic injury. To determine if these changes have an impact in the pharmacokinetics of high extraction drugs (i.e., those drugs which clearance mainly depends on liver blood flow), we studied the pharmacokinetics of a model compound, phenacetin, and of its main metabolite, acetaminophen, in rats 24 h after a high (T1) or a low (T8) SCI, as well as in sham-lesioned controls. After intravenous administration to animals with SCI, reductions in drug clearance and distribution led to an increase in blood concentrations. These alterations were more pronounced after high than after low SCI, as expected from hemodynamic changes. After oral administration, phenacetin blood levels were similar in sham-lesioned and T1-injured animals, but decreased by injury at T8. This is likely due to a reduction in drug absorption which compensates the changes in distribution and elimination induced by injury at T1, whereas it prevails in T8-lesioned animals. Acetaminophen blood concentrations observed after intravenous or oral phenacetin, or after the oral administration of acetaminophen by itself, were increased or reduced, depending on the overall effect of the alterations on absorption, first pass metabolism, distribution and elimination induced by high and low SCI. Results demonstrate that acute SCI significantly alters the pharmacokinetics of high extraction drugs. The outcome of such alterations depends on the level of SCI and on the route of administration.