Dear all,Back to the Top
Does anybody know examples of compounds whose clearance increases with
dose? I am working on a compound which is mainly eliminated renally
(fe>70%) and bile. It seems that at high doses, it's CL is increased.
Route of administration is iv. Any suggestions on what the mechanism
could be?
Many thanks!
B. Parta
[Saturable protein binding? - high dose, low V? - db]
Dear Batul:Back to the Top
As mentioned by David, a likely explanation for increasing CL with dose
is saturable protein binding (e.g., naproxen). However, many other
mechanisms are possible. For example, CL often increases with dose for vitamins
(e.g., riboflavin, ascorbic acid) and IgG antibodies. In the case of
riboflavin, Jusko and Levy demonstrated that CL increases with dose as a result of saturable renal reabsorption (J Pharm Sci. 59(6):765-72, 1970). IgG
elimination often increases with dose (i.e., when very large antibody
doses are given), due to the saturation of the Brambell receptor (also known
as FcRn, FcRp, and FcRB). This receptor protects IgG from intracellular
catabolism (see Brambell et al, Nature 203: 1352-a355, 1964); thus,
saturation of the Brambell receptor results in increases in IgG CL.
J. Balthasar
Joseph P. Balthasar, Ph.D.
Associate Professor
Department of Pharmaceutical Sciences
University at Buffalo
The State University of New York
457B Cooke Hall
Buffalo, New York 14260
Tel: 716-645-2842, x 270
Fax: 716-645-3693
Dear Batul:Back to the Top
Another example of the mechanism cited by Dr. Balthasar is cefuroxime.
You can find the data in this paper:
Ruiz-Carretero P, Merino-Sanjuan M, Nacher A, Casabo VG.
Pharmacokinetic models for the saturable absorption of cefuroxime
axetil and
saturable elimination of cefuroxime. Eur J Pharm Sci. 2004
Feb;21(2-3):217-23.
PMID: 14757493 [PubMed - in process]
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