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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Mechanisms of nonlinear disposition kinetics of sulfamethazine.

Five healthy male subjects received oral doses of 10 and 40 mg/kg of sulfamethazine (SMZ) approximately 14 days apart in a nonrandomized crossover study. Blood and urine samples were collected for at least 24 and 72 hr, respectively. All samples were assayed by the Bratton-Marshall procedure for SMZ and apparent N-acetylsulfamethazine (NSMZ). Recovery of total drug (SMZ + NSMZ) in urine was 88.9% following the low and 79.5% following the high dose. The low and high dose plasma concentration time curves were not readily superimposable (i.e., nonlinear kinetic behavior was observed). The data suggest that several mechanisms contribute to the nonlinearity. Specifically, a dose-dependent decrease in absorption rate displaced the plasma concentration-time curve to the right in some subjects, whereas apparent metabolic clearance (Clm) decreased with increasing dose (estimated assuming dose = amount of SMZ + NSMZ in urine to 72 hr) in all subjects (0.35 ml/min/kg for the low and 0.23 for the high dose). Still greater dose-dependent effects were found when apparent Clm of unbound drug was determined, since free fraction rose from 0.11 to 0.30 over the observed plasma concentration range. Renal clearance (ClR) of Smz appeared to be a complex function of time. In the low dose study it ranged from an average of 0.071 ml/min/kg at 2 hr to 0.146 ml/min/kg at 6 hr after drug. After the high dose comparable values were 0.083 and 0.128. Interindividual variability and pronounced nonlinear kinetics of SMZ after 40 mg/kg suggest that this dose is probably a poor choice for the determination of acetylator phenotype.[1]

References

  1. Mechanisms of nonlinear disposition kinetics of sulfamethazine. du Souich, P., Lalka, D., Slaughter, R., Elvin, A.T., McLean, A.J. Clin. Pharmacol. Ther. (1979) [Pubmed]
 
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