1
s193 PLASMA MORPHINE CONCENTRATION-ANALGESIC RELATIONSHIP IN THE RAT AFTER ! Poster 73 CODEINE AND MORPHINE. Z.R. Chen*l, R. Ritchie*2, R.J. Irvine*2, F. Bochner*l,2, A. Somogyi*l,2 BROWN Mon-Tues (SPON: B. Rounsefell).lDepartment of Clinical Pharmacology, Royal Adelaii ACC Hall E Hospital, 2Department of Clinical and Experimental Pharmacology, Univer Abs No 380 sity of Adelaide, Adelaide 5001, Australia. AIM OF INVESTIGATION: This study investigated the relationship between plasma morphine concentrations and analgesia in rats following separate administration of codeine and morphine. METHODS: Groups of Hooded Wistar rats (male 250-350 g) received intraperitoneal codeine (5-30 mg/kg) or morphine (0.5-1.5 mg/kg). Analgesia was tested by measuring the tail-flick latency time (TFLT) using a model with a reproducibility of greater than 90% (TFLT of 120 seconds was arbitrarily set as 100% maximum response). At the time of the peak analgesic effect (30 minutes for codeine and 45 minutes for morphine), the TFLT was measured and the rats were sacrificed and blood collected for determination of plasma morphine concentrations by HPLC. RESULTS: There was a strong mean dose-TFLT correlation with both codeine (r squaredlO.94, P 0.001, n=5) and morphine (r squared=0.90, p 0.001, n=5). Based on the 50% maximmn response, codeine was only 0.06 times as potent as morphine. Plasma morphine concentrations to produce comparable TFLT's were similar after both codeine and morphine, but showed great variability especially after codeine. Plasma morphine concentrations after morphine correlated with TFLT (r squared=0.56, p 0.001, n=30). However, there was only a poor correlation (r squared=0.27, p 0.01, n=30) between plasma morphine concentrations after codeine and TFLT. CONCLUSION: These results indicate that the analgesic effect of codeine may not be mediated primarily by the in-vivo hepatic formation of morphine. Alternative sites (e.g. brain) for morphine formation after codeine should be considered. PLASMA CONCENTRATIONS AND RENAL CLEARANCES OF MORPHINE-6- AND MORPHINE- Poster 74 3-GLUCURONIDE IN CANCER PATIENTS RECEIVING MORPHINE. A.A. Somo i *l 2 BROWN Mon-Tues R.L. Nation*4, C. Olweny*3, J. Cleary*3, P. Tsirgiotis* *lneh ACC Hall E C. van Crugten*2 and F. Bochner*1,2 (SPON: I. Pilowsky). Department of' i ** Abs No 381 Clinical and Experimental Pharmacolo y, ments of 2Clinical Pharmacology and f University of Adelaide, Depart - Medical Oncology, Royal Adelaide Hospital and, school of Pharmacy, South Australian Institute of Technology, Adelaide, 5001, Australia,. AIM OF INVESTIGATION: One of the metabolites of morphine (Ml, morphine-6-glucuronide (M6G), has been reported to produce analgesia and contribute to adverse effects following morphine administration. This study evaluated the plasma concentrations and urinary elimination of M, M6G and morphine-3-glucuronide (M3G) in cancer patients receiving morphine. METHODS: In 9 cancer patients aged 30 to 76 years who received between 10 and 100 mg morphine orally every four hours, the plasma and urine concentrations of M3G, M6G and M were measured, over an interdosing interval, by a specific HPLC method. RESULTS: The mean (range) plasma concentration ratios of M6G to M were 4.9 (1.6 to 14.51, of MU: to M were 30.3 (10.9 to 63.3) and of M3G to M6G were 6.8 (4.4 to 9.6). In urine, 11.5 (5.4 to 15.01% of the dose was recovered as M6G, 52.4 (39.5 to 68.0)% as M3G and 2.0 (1.3 to 4.01% as morphine. The renal clearances for M6G ranged from 55 to 283 ml/min and did not correlate with creatinine clearance (r2 = 0.41, p ) 0.05, n=7). For M3G, renal clearance ranged from 59 to 185 ml/min and was correlated significantly with creatinine clearance (r2 = 0.80, ~(0.05, n=5). There was a highly significant correlation (r2 = 0.93, p (0.01) between the renal clearance of M3G and that of M6G. Renal clearance of morphine varied widely from 21 to 177 ml/min. In the majority of cases, the renal clearances of M6G and M3G were greater than creatinine clearance. CONCLUSIONS: These data indicate that similar factors operate to alter the renal clearances of M3G and M6G, and that tubular secretion may be an important mechanism for their elimination from the body.

Plasma concentrations and renal clearances of morphine-6- and morphine-3-glucuronide in cancer patients receiving morphine

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Page 1: Plasma concentrations and renal clearances of morphine-6- and morphine-3-glucuronide in cancer patients receiving morphine

s193

PLASMA MORPHINE CONCENTRATION-ANALGESIC RELATIONSHIP IN THE RAT AFTER

!

Poster 73 CODEINE AND MORPHINE. Z.R. Chen*l, R. Ritchie*2, R.J. Irvine*2, F. Bochner*l,2, A. Somogyi*l,2

BROWN Mon-Tues

(SPON: B. Rounsefell).lDepartment of Clinical Pharmacology, Royal Adelaii ACC Hall E

Hospital, 2Department of Clinical and Experimental Pharmacology, Univer Abs No 380 sity of Adelaide, Adelaide 5001, Australia.

AIM OF INVESTIGATION: This study investigated the relationship between plasma morphine concentrations and analgesia in rats following separate administration of codeine and morphine. METHODS: Groups of Hooded Wistar rats (male 250-350 g) received intraperitoneal codeine (5-30 mg/kg) or morphine (0.5-1.5 mg/kg). Analgesia was tested by measuring the tail-flick latency time (TFLT) using a model with a reproducibility of greater than 90% (TFLT of 120 seconds was arbitrarily set as 100% maximum response). At the time of the peak analgesic effect (30 minutes for codeine and 45 minutes for morphine), the TFLT was measured and the rats were sacrificed and blood collected for determination of plasma morphine concentrations by HPLC. RESULTS: There was a strong mean dose-TFLT correlation with both codeine (r squaredlO.94,

P 0.001, n=5) and morphine (r squared=0.90, p 0.001, n=5). Based on the 50% maximmn response, codeine was only 0.06 times as potent as morphine. Plasma morphine concentrations to produce comparable TFLT's were similar after both codeine and morphine, but showed great variability especially after codeine. Plasma morphine concentrations after morphine correlated with TFLT (r squared=0.56, p 0.001, n=30). However, there was only a poor correlation (r squared=0.27, p 0.01, n=30) between plasma morphine concentrations after codeine and TFLT. CONCLUSION: These results indicate that the analgesic effect of codeine may not be

mediated primarily by the in-vivo hepatic formation of morphine. Alternative sites (e.g. brain) for morphine formation after codeine should be considered.

PLASMA CONCENTRATIONS AND RENAL CLEARANCES OF MORPHINE-6- AND MORPHINE- Poster 74 3-GLUCURONIDE IN CANCER PATIENTS RECEIVING MORPHINE. A.A. Somo i *l 2 BROWN Mon-Tues

R.L. Nation*4, C. Olweny*3, J. Cleary*3, P. Tsirgiotis* *lneh ACC Hall E C. van Crugten*2 and F. Bochner*1,2 (SPON: I. Pilowsky). Department of' i ** Abs No 381 Clinical and Experimental Pharmacolo y, ments of 2Clinical Pharmacology and f

University of Adelaide, Depart - Medical Oncology, Royal Adelaide Hospital and, school

of Pharmacy, South Australian Institute of Technology, Adelaide, 5001, Australia,.

AIM OF INVESTIGATION: One of the metabolites of morphine (Ml, morphine-6-glucuronide (M6G), has been reported to produce analgesia and contribute to adverse effects following morphine administration. This study evaluated the plasma concentrations and urinary elimination of M, M6G and morphine-3-glucuronide (M3G) in cancer patients receiving morphine. METHODS: In 9 cancer patients aged 30 to 76 years who received between 10 and 100 mg

morphine orally every four hours, the plasma and urine concentrations of M3G, M6G and M were measured, over an interdosing interval, by a specific HPLC method. RESULTS: The mean (range) plasma concentration ratios of M6G to M were 4.9 (1.6 to 14.51, of MU: to M were 30.3 (10.9 to 63.3) and of M3G to M6G were 6.8 (4.4 to 9.6). In urine, 11.5 (5.4 to 15.01% of the dose was recovered as M6G, 52.4 (39.5 to 68.0)% as M3G and 2.0 (1.3 to 4.01% as morphine. The renal clearances for M6G ranged from 55 to 283 ml/min and did not correlate with creatinine clearance (r2 = 0.41, p ) 0.05, n=7). For M3G, renal clearance ranged from 59 to 185 ml/min and was correlated significantly with creatinine clearance (r2 = 0.80, ~(0.05, n=5). There was a highly significant correlation (r2 = 0.93, p (0.01) between the renal clearance of M3G and that of M6G. Renal clearance of morphine varied widely from 21 to 177 ml/min. In the majority of cases, the renal clearances of M6G and M3G were greater than creatinine clearance. CONCLUSIONS: These data indicate that similar factors operate to alter the renal clearances of M3G and M6G, and that tubular secretion may be an important mechanism for their elimination from the body.