ALPHA(1)-ACID GLYCOPROTEIN CONCENTRATIONS AND CEREBROSPINAL-FLUID DRUG DISTRIBUTION AFTER SUBARACHNOID HEMORRHAGE

Study Objective. To test the hypothesis that changes in oil-acid glyco protein (AAG) concentration alter central nervous system (CNS) drug di stribution after subarachnoid hemorrhage. Design. Two-phase, prospecti ve study Setting. University-associated medical center. Patients. Twen ty-one patients with subarachnoid hemorrhage. Intervention. In phase I , serum AAG concentrations of patients with subarachnoid hemorrhage we re measured serially and compared with those in 21 controls undergoing elective neurosurgical procedures. In phase II, nimodipine was the ph armacologic probe to determine the relationship between drug distribut ion into the CNS and changes in AAG concentration. Measurements and Ma in Results. Serum and cerebrospinal fluid (CSF) samples were collected from patients with subarachnoid hemorrhage treated with nimodipine an d used to measure total and unbound drug concentrations.: Concentratio ns of AAG were 39% higher in patients than in controls preoperatively. They decreased significantly by 24 hours after surgery in patients an d increased in controls. In both groups the concentrations were higher :than reported normal values. During the period of reduced AAG concent ration, calculated unbound nimodipine concentrations were 3-fold highe r (p<0.05) than at later periods, with a trend toward higher total con centrations. Overall, mean CSF nimodipine concentration was 6.4% of me an serum total concentration. The CSF concentrations decreased as AAG concentrations increased, independent of serum concentrations (r = -0. 52, p<0.02). Conclusion. Concentrations of AAG change after subarachno id hemorrhage and are transiently influenced-by surgery. Unbound drug concentration increases when AAG concentrations decrease, whereas CSF concentrations decrease when AAG concentrations increase. These prelim inary findings suggest that changes in AAG concentrations can alter un bound serum nimodipine concentrations and-may affect CSF drug distribu tion.