The relation of choroid plexus carbonic anhydrase activity to cerebrospinal fluid formation: study of three inhibitors in cat with extrapolation to man.
Drugs which inhibit carbonic anhydrase (CA) reduce cerebrospinal fluid (CSF) flow. This study relates the inhibition of CSF flow in cats after 1 to 30 mg/kg of methazolamide, acetazolamide or benzolamide (inhibitors of differing pharmacokinetic properties) to plasma and choroid plexus levels of these drugs. From plasma concentrations of unbound drug and the dissociation constants for the interaction of drugs with choroid plexus CA, it is shown that the concentration of residual active CA in choroid plexus of cats must be reduced from approximately 22 microM to the range of 5 to 10 nM to reduce CSF flow significantly. This represents at least 99.95% inhibition of CA of choroid plexus. This level of inhibition was achieved by an i.v. dose of 30 mg/kg of methazolamide, acetazolamide or benzolamide, whereas doses of 10 mg/kg of methazolamide or acetazolamide did not significantly decrease mean residual CSF flow. The data suggest that it is the residual flow after inhibition, not the absolute or percentage of decrease in flow, which should be used to evaluate the effectiveness of CA inhibition, because of the variability in individual control rates. Maximal effects of CA inhibition in cat reduce flow to 9 to 11 microliter/min from a mean of 21.7 microliter/min. In choroid plexus of man, the CA concentration is, at most, 40% that of cat. An attempt has been made to use CA concentration, drug binding data and other pharmacokinetic factors in predicting appropriate choices of drug and dose for man, extrapolating from the data for cats. These predictions are compared to existing data for plasma levels or CSF effects of CA inhibitors in man.
D000086:Acetazolamide / Q000494:pharmacology; D000818:Animals; D001574:Benzolamide / Q000494:pharmacology; D002257:Carbonic Anhydrase Inhibitors / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D002415:Cats; D002555:Cerebrospinal Fluid / Q000187:drug effects* / Q000378:metabolism; D002831:Choroid Plexus / Q000201:enzymology* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008704:Methazolamide / Q000494:pharmacology
D002257:Carbonic Anhydrase Inhibitors; D001574:Benzolamide; D000086:Acetazolamide; D008704:Methazolamide