Kinetics of drug action in disease states. XXVII. Effect of experimental renal failure on the pharmacodynamics of zoxazolamine and chlorzoxazone.
The purpose of this investigation was to determine whether the pharmacodynamics of the centrally acting skeletal muscle relaxants zoxazolamine (ZOX) and chlorzoxazone (CZX) are altered in renal failure. Male Lewis rats with renal failure due to bilateral ligation of ureters and sham-operated controls (ZOX and CZX), as well as rats with uranyl nitrate-induced renal dysfunction and saline-injected controls (ZOX only), received an infusion of ZOX or CZX until onset of loss of righting reflex. Drug concentrations in serum, brain and cerebrospinal fluid at that time were substantially lower in animals with renal failure or dysfunction than in normal controls. The ZOX concentrations in the cerebrospinal fluid correlated negatively with indices of renal function (serum creatinine and urea concentrations). Administration of a concentrated dialyzate of serum from rats with uranyl nitrate-induced renal dysfunction to normal animals also decreased the concentrations of ZOX at onset of loss of righting reflex. Thus, the sensitivity of the central nervous system of rats to the depressant action of ZOX and CZX is significantly increased by renal failure. This effect appears to be mediated, at least in part, by an endogenous, dialyzable substance that accumulates in the blood of rats with impaired renal function.
Yasuhara
M
M
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, Amherst.
Levy
G
G
D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D001583:Benzoxazoles / Q000493:pharmacokinetics*; D002753:Chlorzoxazone / Q000493:pharmacokinetics*; D008026:Ligation; D008297:Male; D009125:Muscle Relaxants, Central / Q000493:pharmacokinetics*; D051381:Rats; D011917:Rats, Inbred Lew; D014502:Uranyl Nitrate; D014513:Ureter; D015049:Zoxazolamine / Q000493:pharmacokinetics*
D001583:Benzoxazoles; D009125:Muscle Relaxants, Central; D014502:Uranyl Nitrate; D015049:Zoxazolamine; D002753:Chlorzoxazone