Nephrology Dialysis Transplantation, Vol 14, Issue 4 903-909, Copyright © 1999 by Oxford University Press
C Pauli-Magnus, U Hofmann, G Mikus, U Kuhlmann and T Mettang
Background. Conjugation with glucuronic acid
represents the major route of biotransformation of morphine. The
glucuronides morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G)
are eliminated via the kidneys. Therefore, chronic
renal failure should affect the disposition of M3G and M6G. Numerous
patients undergoing long-term continuous ambulatory peritoneal dialysis
(CAPD) require pain treatment with morphine. There are only limited data
available about the disposition of morphine and its active metabolites M6G
and M3G in patients on CAPD. We therefore investigated the pharmacokinetics
of morphine and its metabolites in CAPD patients. Methods.
This was a single intravenous dose pharmacokinetic study in 10
CAPD patients (1 female, 9 male, age 31-69 years). Morphine-hydrochloride
(Mo) (10 mg) was administered intravenously. Serum, urine, and dialysate
samples were collected during 24 h. GC-MS-MS and HPLC-MS methods were used
to quantify respectively morphine and morphine glucuronides.
Results. While systemic clearance of morphine
(1246±240 ml/min) was in the range observed in patients with
normal kidney function, both M3G and M6G showed substantial accumulation.
The area under the concentration-time curve (AUC) ratio of M3G:Mo
(33.4±7.1) and of M6G:Mo (12.2±3.2) was 5.5 and 13.5
times higher than in patients with normal kidney. Renal clearances of
morphine, M3G, and M6G (morphine 3.0±2.2 ml/min; M3G
3.9±2.2 ml/min; M6G 3.6±2.2 ml/min) and dialysate
clearances (morphine 4.1±1.3 ml/min; M3G 3.2±0.7
ml/min; M6G 3.0±0.8 ml/min) were extremely low. Therefore the
accumulation of M6G and M3G is readily explained by kidney failure which is
not compensated by CAPD. Conclusion. Accumulation of
M3G and M6G is due to the substantially lowered clearance by residual renal
function and peritoneal dialysis. In view of the accumulation of potential
active metabolites, subsequent investigations have to assess the frequency
of side-effects in patients on CAPD. Keywords:
morphine; morphine glucuronides; peritoneal dialysis;
pharmacokinetics; renal failure
ORIGINAL ARTICLES
Pharmacokinetics of morphine and its glucuronides following intravenous administration of morphine in patients undergoing continuous ambulatory peritoneal dialysis
Dr Margarete Fischer-Bosch-Institut of Clinical Pharmacology, Auerbachstr. 112, 70376 Stuttgart, Germany; Robert Bosch Hospital, Department of Internal Medicine, Division of Nephrology, Stuttgart, Germany; Corresponding author
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