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Dear all,
How to explain the PK of a drug which is undergoing active renal tubular
secretion, yet the PK is not affected by the concomitant administration of
cimetidine and probenecid? What else could be done to validate it?
I am perplexed by the lack of interaction finding in a randomized 3-way
crossover study, in the presence of high doses of cimetidne and probenecid,
The 3 crossovers are: a single oral dose of 3 mg of the drug alone
(treatment A), 400 mg cimetidine given 2 hours before, and given at the same
time as the drug and 400 mg cimetidine give 6 hours later (treatment B), and
1000 mg probenecid 2 hours before and 500 mg probenecid given at the same
time as the drug (treatment C).
For the drug in question, no metabolite has been identified and up to 80% of
the intact drug has been recovered from the urine following a single oral
dose. The renal clearance based on urinary recovery is 20 L/h, which
exceeds glomerular filtration of 7.5 L/h, hence active renal secretion is
implicated. Since the drug has both acidic pKa (8.3) and basic pKa (9.8),
either anionic or cationic renal transporters may be implicated.
Kind regards,
Charles Oo
Hoffmann-La Roche Inc.
340, Kingsland Street
Nutley, NJ 07110-1199
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My guess is that P-gp could be involved - This is known to exist in
proximal renal tubules as you probably know.
Perhaps confirm this for your drug in vitro using a monolayer efflux
system with say an MDR1-MDCKII cell line with and without known P-gp
inhibitor(s), e.g. GF120918 (see JW Polli et al. J Exp Pharmacol Ther
299:620-628; 2001).
(There could also be a yet to be discovered specific transporter as is
suspected for other compounds, e.g. thyroxine.)
Cheers,
BC
Bruce CHARLES
BPharm(Hons), GradDipBusAdmin, PhD, MPS
Associate Professor
Director, The Australian Centre for Paediatric Pharmacokinetics
University of Queensland, School of Pharmacy, QLD 4072
Australia
b.charles.-at-.pharmacy.uq.edu.au
http://www.uq.edu.au/pharmacy/charles.html
http://www.mater.org.au/pharm/accp/index.htm
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)