Steady-state cerebrospinal fluid transfer of verapamil and metabolites in patients with schizophrenia.
Cerebrospinal fluid (CSF) and plasma levels of verapamil and its two metabolites, norverapamil and D-620, were measured in seven patients with schizophrenia under steady-state conditions. Simultaneous sampling of CSF and plasma just before the dose during week 4 of the trial showed that verapamil, norverapamil, and D-620 partition in the CSF and reflect 7%, 5%, and 12% of the corresponding levels in plasma, respectively. There was a significant decrease in the mean unbound fraction of verapamil in schizophrenic patients as compared with normal subjects (0.058 vs. 0.11; p less than 0.001). Estimates of the mean unbound fraction obtained from CSF/plasma verapamil concentrations and the pH partition hypothesis showed excellent agreement with that measured by equilibrium dialysis (0.055 vs. 0.058) in these patients. Although systemic pool protein concentrations in schizophrenic patients were within normal range, an excellent positive correlation was observed between the ratio of the bound/free verapamil concentration and alpha 1-acid glycoprotein levels (r = 0.86; p less than 0.05). Determination and development of correlations between plasma and CSF may enhance our understanding of the central nervous system effects of verapamil.
Narang
P K
PK
Warren G. Magnuson Clinical Center Pharmacy and Clinical Neuroscience Branch, National Institute of Mental Health, Bethesda, Md.
Blumhardt
C L
CL
Doran
A R
AR
Pickar
D
D
D000284:Administration, Oral; D000328:Adult; D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier; D002851:Chromatography, High Pressure Liquid; D004311:Double-Blind Method; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D008297:Male; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism*; D014700:Verapamil / Q000031:analogs & derivatives / Q000097:blood / Q000134:cerebrospinal fluid* / Q000378:metabolism / Q000627:therapeutic use
D001798:Blood Proteins; C016906:alpha-(3-aminopropyl)-3,4-dimethoxy-alpha-(1-methylethyl)benzeneacetonitrile; C016904:norverapamil; D014700:Verapamil