Stepwise determination of multicompartment disposition and absorption parameters from extravascular concentration-time data. Application to mesoridazine, flurbiprofen, flunarizine, labetalol, and diazepam.
When disposition is monoexponential, extravascular concentration-time (C, t) data yield both disposition and absorption parameters, the latter via the Wagner-Nelson method or deconvolution which are equivalent. Classically, when disposition is multiexponential, disposition parameters are obtained from intravenous administration and absorption data are obtained from extravascular C, t data via the Loo-Riegelman or Exact Loo-Riegelman methods or via deconvolution. Thus, in multiexponential disposition one assumes no intrasubject variation in disposition, a hypothesis that has not been proven for most drugs. Based on the classical two- and three-compartment open models with central compartment elimination, and using postabsorptive extravascular C, t data only, we have developed four equations to estimate k10 when disposition is biexponential and two other equations to estimate k10 when disposition is triexponential. The other disposition rate constants are readily obtained without intravenous data. We have analyzed extravascular data of flurbiprofen (12 sets), mesoridazine (20 sets), flunarizine (5 sets), labetalol (9 sets), and diazepam (4 sets). In the case of diazepam intravenous C, t data were also available for analysis. After disposition parameters had been estimated from the extravascular data the Exact Loo-Riegelman method with the Proost modification was applied to the absorptive extravascular data to obtain AT/VP as a function of time. These latter data for each subject and each drug studied were found to be fitted by a function indicating either simple first-order absorption, two consecutive first-order processes, or zero-order absorption. After absorption and disposition parameters had been estimated, for each set of extravascular data analyzed, a reconstruction trend line through the original C, t data was made. The new methods allow testing of the hypothesis of constancy of disposition with any given drug. There is also a need for new methods of analysis since the majority of drugs have no marketed intravenous formulation, hence the classical methods cannot be applied.
College of Pharmacy, University of Michigan, Ann Arbor 48109.
J G
JG
Wagner
D A
DA
Ganes
K K
KK
Midha
I
I
Gonzalez-Younes
J C
JC
Sackellares
L D
LD
Olson
M B
MB
Affrime
J E
JE
Patrick
D000465:Algorithms; D003975:Diazepam / Q000493:pharmacokinetics; D005444:Flunarizine / Q000493:pharmacokinetics; D005480:Flurbiprofen / Q000493:pharmacokinetics; D006801:Humans; D007741:Labetalol / Q000493:pharmacokinetics; D008653:Mesoridazine / Q000493:pharmacokinetics; D008962:Models, Theoretical; D010599:Pharmacokinetics
D005480:Flurbiprofen; D008653:Mesoridazine; D003975:Diazepam; D007741:Labetalol; D005444:Flunarizine