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The following message was posted to: PharmPK
PK Group:
I am evaluating a drug in a population of nephrotic disease patients,
with GFRs between 52 ml/min and normal renal function. The drug is
metabolized (phase I demethylation or hydroxylation and then phase II
sulfation or glucuronidation). The drug is known to be eliminated
through the kidneys as the metabolites, not the parent drug. My
analysis shows that Albumin and GFR contribute to the AUC. I would have
predicted the albumin (as albumin declines, AUC declines) secondary to
increased drug available for metabolism (drug is 98% bound). I am at a
loss to explain the GFR effect (decrease in GFR, see increase in AUC).
Based on my data, it does not appear that there are any oddities in the
plasma concentrations to suggest any type of recycling. The metabolic
ratios for the demethylated metabolite (the metabolite we measured) are
between 1.2 and 5. So, I am a little hesitant to suggest a reduction in
metabolic capabilities secondary to renal disease. The Cl/F in these
patients was 2-3 fold greater than reported for healthy patients. We
have urine but have not assayed the samples. Any ideas would be greatly
appreciated.
Sincerely,
Melanie S. Joy, Pharm.D., FCCP
Associate Professor
UNC School of Medicine
Division of Nephrology and Hypertension
UNC Kidney Center
CB #7155, 7005 Burnett Womack Building
Chapel Hill, NC 27599-7155
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The following message was posted to: PharmPK
Hi Melanie,
There is a new data coming out that uremia in renal disease may
contribute to decreased transporter functions, particularly P-gp (some
evidence on OATP2). Blocking of P-gp would increase F at intestine and
decrease biliary clearance and possibly (not as much info) renal
clearance.
If metabolites are renally transported, their concentrations could go up
(decreased elimination).
Susan
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