Drug disposition viewed in terms of the fractal volume of distribution.
OBJECTIVE
(i) Evaluate the predictive performance of the fractal volume of drug distribution, v(f), (Pharm. Res.18, 1056, 2001), (ii) develop the concept of the fractal clearance, CLf, which is the clearance analogue of v(f), (iii) examine the utility of CLf in allometric studies, (iv) develop allometric relationships for the elimination half-life, t1/2, and (v) evaluate the use of v(f) and CLf in predicting the volume of drug distribution, Vap, clearance, CL, and elimination half-life, t1/2.


METHODS
Estimates for v(f) of various drugs were obtained and correlated with body mass using data only from animal species. A comparison was made between the predicted and actual v(f) values for humans. For a variety of animal species CLf values were estimated from the equation: [equation: see text]. The allometric equations developed using CLf were compared with other allometric approaches. Allometric equations were also developed for t1/2 utilizing the allometric relationships of v(f) and CLf,


RESULTS
The predicted estimates of v(f) were very close to the actual values and the correlation exhibited favorable statistical properties. The values of the allometric exponents for CLf were found to be close to 0.75. The predictive performance for CL using the allometric equations for CLf in conjunction with the rule of exponents was found to be better than the currently considered most accurate allometric approaches. The values of the allometric exponents for t1/2 were found to be close to 0.25


CONCLUSIONS
The predictive ability of v(f) is high; predictions for Vap based on v(f) values are better than the current approaches. CLf expressed a good behavior both in prospective and retrospective analysis. The allometric exponents, 0.75, 0.25 for CLf and t1/2, respectively, agree with the theoretical expected values.
Karalis
Vangelis
V
School of Pharmacy, University of Athens, Greece.
Macheras
Panos
P
D000818:Animals; D019540:Area Under Curve; D003627:Data Interpretation, Statistical; D017709:Fractals; D006207:Half-Life; D006801:Humans; D008954:Models, Biological; D010599:Pharmacokinetics; D011237:Predictive Value of Tests; D013045:Species Specificity