Diphenylhydantoin elimination kinetics in overdosed children

Abstract

Diphenylhydantoin (DPH) elimination was studied in 4 overdosed children who presented with serum concentrations ranging from 44 to 76 mg/l. Serum was assayed for DPH and urine was assayed for both DPH and 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). The serum and urine data were subjected to simultaneous computer nonlinear regression analysis using a one-compartment pharmacokinetic model, which accounts for much of the known disposition kinetics of DPH. Computed values for the apparent in vivo Michaelis-Menten constants, K-M and V max, were compared with values derived from data in the literature for normal adult subjects. A trend toward relatively lower K-M and higher V max/K-M values was seen in children. Patients with higher V max values had greater urinary excretion rates of HPPH which, at high serum levels of DPH, were relatively constant except for an apparent diurnal rhythm. The time of onset of DPH toxicity in the children was related to the magnitude by which the rate of DPH administration exceeded the V max values.

Pharmacokinetics and pharmacodynamics of methylprednisolone when administered at 8 AM versus 4 PM

“…PCNONLJN was also used in the fitting of the individual MPS concentration-time data to equation 3: (3) in which C Mps is the MPS concentration at time t,. is the MPS concentration at time zero, and k is the terminal slope.…”

“…On the baseline day, approximately 8 ml blood was withdrawn every 2 hours and placed into heparinized tubes. During the study days involving drug administration, approximately 8 ml blood was obtained just before and at ¼, ½, 1, 1½, 2,3,4,6,8,10,12,14,16,18,20,22, and 24 hours after drug administration. In addition, 4 ml blood was drawn into EDTA (Na 2 ) tubes at 0, 1,2, 4, 8, 12, 16, 20, and 24 hour after drug administration for the determination of helper T cell (CD4 lymphocyte) counts.…”

“…The CL of methylprednisolone was calculated from the following equation: (2) PCNONLJN was also used in the fitting of the individual MPS concentration-time data to equation 3: (3) in which C Mps is the MPS concentration at time t,.…”

“…However, these agents may be administered as divided doses or even as a single evening dose in those conditions requiring adrenal suppression. 1 Numerous drugs, including theophylline, 2 phenyloin, 3 and cisplatin, 4 have demonstrated temporal variations in their pharmacokinetics. This is not surprising because it has been shown in animals that both hepatic drug-metabolizing activities and renal clearance (CL R ) mechanisms exhibit circadian variations.…”

“…k is the terminal slope, and V is the volume of distribution. This equation assumes negligible interconversion between methylprednisolone and its metabolite mcthylprcdnisone.The CL of methylprednisolone was calculated from the following equation:PCNONLJN was also used in the fitting of the individual MPS concentration-time data to equation 3: (3) in which C Mps is the MPS concentration at time t,. is the MPS concentration at time zero, and k is the terminal slope.…”