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1.  Allometric scaling of xenobiotic clearance: Uncertainty versus universality 
AAPS PharmSci  2001;3(4):30-43.
Statistical analysis and Monte Carlo simulation were used to characterize uncertainty in the allometric exponent (b) of xenobiotic clearance (CL). CL values for 115 xenobiotics were from published studies in which at least 3 species were used for the purpose of interspecies comparison of pharmacokinetics. The b value for each xenobiotic was calculated along with its confidence interval (CI). For 24 xenobiotics (21%), there was no correlation between log CL and log body weight. For the other 91 cases, the mean±standard deviation of the b values was 0.74±0.16; range: 0.29 to 1.2. Most (81%) of these individual b values did not differ from either 0.67 or 0.75 at P=0.05. When CL values for the subset of 91 substances were normalized to a common body weight coefficient (a), the b value for the 460 adjusted CL values was 0.74; the 99% CI was 0.71 to 0.76, which excluded 0.67. Monte Carlo simulation indicated that the wide range of observed b values could have resulted from random variability in CL values determined in a limited number of species, even though the underlying b value was 0.75. From the normalized CL values, 4 xenobiotic subgroups were examined: those that were (i) protein, and those that were (ii) eliminated mainly by renal excretion, (iii) by metabolism, or (iv) by renal excretion and metabolism combined. All subgroups except (ii) showed a b value not different from 0.75. The b value for the renal excretion subgroup (21 xenobiotics, 105 CL values) was 0.65, which differed from 0.75 but not from 0.67.
doi:10.1208/ps030429
PMCID: PMC2751218  PMID: 12049492
allometric scaling; body-weight exponent; clearance; metabolism; metabolic rate; pharmacokinetics; Monte Carlo simulation; power law
2.  Maturation and growth of renal function: Dosing renally cleared drugs in children 
AAPS PharmSci  2000;2(1):22-28.
A model was developed that characterized the maturation and growth of the renal function parameters (RFPs) glomerular filtration rate (GF), active tubular secretion (AS), and renal plasma flow (QR). Published RFP values were obtained from 63 healthy children between the ages of 2 days and 12 years. Maturation over time was assumed to be exponential from an immature (RFPim) to a mature (RFPma) level; for growth, RFPim and RFPma were assumed to follow the allometric equation: RFP(age, W)=aWbe−kmat*age+cWb(1−e−kmat*age), where W is body weight, kmat is the maturation rate constant, b is the body weight exponent, and a and c are RFPim and RFPma at unit W. The model-based equation was fitted to the age-W, RFP values by a nonlinear least-squares method. For GF, the maturation half-life was 7.9 months (90% maturation, 26 months), the body weight exponent was 0.662, and the ratio c/a (which reflected the magnitude of the maturation influence) was 3.1. For AS and QR, the maturation half-lives were about 3.8 months and the ratio c/a was about 1.8. For renally eliminated drugs, the model can be used to estimate dosing regimens that are based on the adult dosing regimen and the age and weight of the child.
doi:10.1208/ps020103
PMCID: PMC2750998  PMID: 11741219
Renal Function

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