Eur J Clin Pharmacol (1991) 41:375 378 European .g.... I of I~l]~JJi~(~@ J] © Springer-Verlag 1991

Pharmacokinetics of intramuscular nicomorphine and its metabolites in man P. M. Koopman-Kimenai l , T. B. Vree I'2, L. H. D. J. Booij 2, R. Dirksen 2, and G. M. M. Nij huis 2 Departments of Clinical Pharmacy and 2 Anaesthesiology, Academic Hospital Nijmegen Sint Radboud, Nijmegen, The Netherlands Received: November 23, 1990/Accepted in revised form: February 16, 1991

Summary. A f t e r i. m. injection n i c o m o r p h i n e is relatively slowly a b s o r b e d f r o m the muscular d e p o t and is f o u n d in the serum for approximately 1 h. T h e rate of absorption differs b e t w e e n patients and governs the overall p h a r m a cokinetic profile of the c o m p o u n d . T h e relative A U C s were n i c o m o r p h i n e 1 8 % , 6-nicotinoylmorphine 1 7 % , and m o r p h i n e 65 %. N i c o m o r p h i n e and 6-nicotinoylmorphine have significantly higher A U C s after i.m. injection than after i.v. injection, while the A U C of m o r p h i n e and the total A U C show no difference b e t w e e n the two m o d e s of administration.

Key words: N i c o m o r p h i n e ; 6-nicotinoylmorphine, morphine, intramuscular administration, metabolism, absorption, p h a r m a c o k i n e t i c s

W h e n given intravenously, n i c o m o r p h i n e (3,6-dinicotin o y l m o r p h i n e , D N M ) rapidly disappears f r o m the blood and forms the metabolites 6-nicotinoylmorphine and m o r phine, as r e p o r t e d elsewhere [1]. T h e half-life of n i c o m o r phine varies b e t w e e n 1 and 3 min, whereas that of its metabolite 6-nicotinoylmorphine varies b e t w e e n 5 and 15 rain, and the half-life of the final metabolite m o r p h i n e is a b o u t 190 min. A f t e r i. m. n i c o m o r p h i n e n o n e might be expected to be detectable in s e r u m because of its rapid elimination. The kinetics of circulating n i c o m o r p h i n e has n o w b e e n studied in 8 patients u n d e r c o m b i n e d general and epidural anaesthesia, who were given 20 mg n i c o m o r p h i n e intramuscularly. In order to m e a s u r e n i c o m o r p h i n e and its metabolites in serum, a sensitive H P L C assay with electrochemical and U V detection [2] has b e e n developed.

Subjects and methods

(American Society of Anaesthesiologists) Class 1, aged 25 to 50 y (mean [SD] 40[9] y), and of normal body weight (mean 62[6] kg) and height (mean 16616] cm) were included. Patients were excluded with liver or kidney dysfunction, known allergic reactions, habitual use of opiates or opiate antagonists, and an expected blood loss greater than 500 ml during surgery.

Anaesthesia The premedication was 10 mg diazepam p.o. given 60-120 min before the induction of anaesthesia. An i.v. drip was started in a lower arm vein, a blood pressure cuff and a finger plethysmograph were attached, and an epidural catheter (L2-L3) and an arterial catheter in the radial artery were inserted. Epidural anaesthesia was produced with 0.5 % bupivacaine with adrenaline, a test dose of 3 ml being followed by a full dose of 11 ml times the body length in metres. The resulting block was tested 15 min after injection of the full dose. Maintenance of epidural analgesia during and after surgery was obtained with 0.25 % bupivacaine (4-6 ml.h-~) given epidurally via an infusion pump. Induction of general anaesthesia with thiopentone ( 3 4 mg.kg-~) was followed by relaxation with vecuronium bromide (0.1 mg.kg- ~) and the insertion of an orotracheal tube (lignocaine ointment 2 %) Anaesthesia was maintained by inhalation of 67% nitrous oxide in oxygen. Relaxation was maintained with vecuronium bromide 1-2 mg i.v. When needed, respiration was controlled at an end-tidal PCO2 between 4 and 4.5 vol %. Concomitant therapy was noted on the medication form. Care was taken not to use any narcotic analgesic except nicomorphine. The patients received 20 mg nicomorphine (Vilan R) intramuscularly in the deltoid muscle (1.5 cm deep). The nicomorphine injection was given when the starting procedures for anaesthesia and surgery had finished and the patient's condition had stabilized.

Sampling Blood samples were taken just before and 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20, 30, 45, 60, 90, 120,240, 360, and 480 min after the nicomorphine injection.

Patients Analysis of nicomorphine Eight women scheduled for minor lower abdominal surgery (laparoscopy) were studied. The study received the approval of the Ethics Committee of the Sint Radboud Hospital. Only patients of ASA

The blood samples were analyzed by HPLC as described elsewhere {2].

376

E M. Koopman-Kimenai et al.: Nicomorphine kinetics ;erum conc (ng.m1-1)

Serum conc (ng.m1-1)

I0C

1001

i 1

~ , ~ ' ~ m i n )

'~" ....."¢""''"~''" ""9.... 6MNM(t~16rain)

f

~

r"

........... NM/t !.~ 20 rain) DNM ( t ~ 20rain)

DNM(t~ 7 rain) 1.

1

5

o

I

20

1

40

I

60

a

I

80

I

100

I

o

120

Time(rain)

I

20

I

40

b

I

60

I

80

I

100

I

120

Time (rain)

Fig.la, b.

Serum concentration-time curves of nicomorphine (DNM) and its metabolites 6-nicotinoylmorphine (6MNM) and morphine (M) in Patient 5 after i.m. nicomorphine 20 rag. a Nico-

morphine is rapidly absorbed from the muscle mass. b The right panel from Patient i shows relatively slow absorption of nicomorphine

Drugs

serum concentration was achieved 20 min after administration and the halfdife was 20 rain. The metabolite 6MNM appeared immediately in serum in a concentration similar to that of the parent drug. Its maximum serum concentration was achieved 30 min after administration. Nicomorphine and 6-nicotinoylmorphine had identical halflives of 20 min. The metabolite morphine appeared in the serum after 10 min, achieved its maximum concentration after 60 min, and was eliminated with a half-life of 110 min. The pharmacokinetics of nicomorphine and its metabolites in the 8 patients are summarised in Table 1. There was wide variability amongst the various patients. The A U C s of nicomorphine and its metabolites and the percentage of the total A U C (sum of the three compounds) after i.m. administration are also presented in Table 1. The AUCs of the parent drug and the metabolite 6-mononicotinoylmorphine were similar (181101% vs 17141%) and were smaller than that of morphine (651111%). The percentage of the total A U C for morphine was linearly and inversely related to the percentage of the total A U C of the parent drug nicomorphine (r = -0.62). The correlation coefficient between the relationship for the AUCs of 6-nicotinoylmorphine and nicomorphine was much lower (r = 0.014). The relative systemic availability of nicomorphine and each of its two metabolites after i.m. and i.v. administration are shown in Table 2 (data from 1). Nicomorphine and 6-nicotinoylmorphine had significantly higher AUCs after i. m. than i. v. injection, while the AUCs of morphine and the total A U C showed no difference between the two modes of administration.

Nicomorphine (VilanR), 6-mononicotinoylmorphine, and morphine were obtained from Nourypharma (Oss, The Netherlands).

Pharmacokinetic data processing Peak plasma concentrations (Cm,x)and times to peak concentrations (tmax) were tabulated. Areas under the plasma concentration-time curves (AUC) and the first moment of the curves (AUMC) were calculated by the linear trapezoidal method. Curve fitting was carried out by means of ELSMOS. Systemic clearance (CL) was calculated as Dose/AUC. Steady-state apparent volume of distribution (V~s) was calculated as Dose.AUMC.AUC -z. Mean residence times (MRT) were calculated as AUMC.AUC 1.

Results

The plasma concentration-time curves of nicomorphine and its metabolites after i. m. nicomorphine differed from patient to patient. Examples of nicomorphine curves are shown in Fig. 1. They demonstrate variability in the absorption of nicomorphine from the muscle. The serum concentration-time curves of nicomorphine and its metabolites 6-nicotinoylmorphine and morphine in Patient 5 are shown in Fig. 1 (left-hand panel). Nicomorphine was rapidly absorbed from the muscle depot and had an apparent half-life of 7 min. The maximum serum concentration was achieved 4 min after administration. The metabolite 6-nicotinoylmorphine was immediately detected in serum, its maximum concentration being achieved 5 rain after administration; its apparent half-life of elimination was 16 min. The metabolite morphine appeared after 2 min in the serum and was eliminated with a half-life of 45 min, In Patient 1 (Fig. i right-hand panel) nicomorphine was slowly absorbed from the muscle depot. The maximum

Discussion

The study has shown that nicomorphine was unexpectedly present in serum for a relatively long period, varying from 30 to 90 min. In some patients its absorption was irregular

377

P M. Koopman-Kimenai et al.: Nicomorphine kinetics Table 1. Pharmacokinetics of nicomorphine and its metabolites after intramuscular administration to 8 female patients Subject

Nicomorphine Cm,x(ng.ml 1) tma×(min) AUC (nmol. 1-~.h) AUC (% total AUC) t~/2(min) MRT (min) CL (ml .rain-~) Vss (1) 6-nicotinoylmorphine Cm~ (rig .m1-1) tm~ (min) AUC (nmol •1- ~-h) AUC (% total AUC) t1/2(min) MRT (rain) morphine Cm,x(ng.ml i) tmax(min) AUC (nmol-1- ~-h) AUC (% total AUC) t~/2(min) MRT (rain)

mean (SD)

1

2

3

4

5

6

7

8

43.8 20 64 9.1

95.7 45 198 40.1

81.8 5 95 11.2

123 5 78 12.3

194 4 80 13.3

481 2 134 21.7

110 8 112 21.4

58.2 20 83 15.9

148 (142) 14 (15) 106 (43) 18 (10)

20 38 11 0.39

18 44 3 0.15

11 31 7 0.22

21 28 9 0.24

7 12 8 0.10

17 28 5 0.14

17 27 6 0.16

19 35 8 0.28

16 (5) 30 (9) 7 (2) 0.21 (0.09)

46.7 30 131 18.6

32.7 45 76 15.4

42.9 10 77 9.1

75.7 5 114 18.0

107 5 102 16.9

58.1 15 120 19.4

56.0 5 115 22.1

34.1 25 92 17.5

57 (25) 18 (15) 103 (20) 17 (4)

20 49

18 39

25 40

23 40

16 23

17 38

18 43

25 45

20 (4) 40 (7)

47.1 60 510 72.3 110 173

34.4 65 219 44.4 40 74

34.3 30 677 79.7 180 301

47.2 60 443 69.7 78 125

53.7 45 419 69.7 45 115

38.5 45 363 58.8 86 143

40.5 30 294 56.5 67 122

42.3 60 350 66.6 70 125

42 (7) 49 (14) 409 (140) 65 (11) 85 (45) 147 (68)

Table 2. Comparison of the systemic availability of nicomorphine and its metabolites after intramuscular and intravenous administration AUC (nmol.1-1. h)

Mode of administration 20 mg i.m. 20 mg i. v.a

P

i.m./i, v. x 100 %

AUCDNM AUC6MNM AUCM AUC~ot~

105 (43.2) 38.7(15.6) 103 (20.3) 68.7(12.4) 409 (140) 515 (195) 618 (117) 622 (208)

0.008 0.023 0.784 0.315

271 150 79 99

Wilcoxons test P < 0.05. Data from Reference 1

and may well have depended in part upon the site and depth of the individual muscular depot and the blood flow to the muscle. The apparent tl/a of elimination, which is equal to the apparent t~/2 of absorption because of rate limitation, varied between 7 and 20 min. The metabolite 6-nicotinoylmorphine was immediately detected in the serum, while 3-nicotinoylmorphin e could not be detected, as after i.v. injection [1]. The serum concentration of 6-nicotinoylmorphine followed that of nicomorphine and this behaviour, too, was similar to that after i.v. injection. The half-life of formation of 6-nicotinoylmorphine was of the same magnitude as the absorption half-life of nicomorphine (Table 1). In Patients 3 and 5, in w h o m the drug was absorbed rapidly, and the overall picture resembled that of an i.v. injection, there was biphasic elimination of 6-mononicotinoylmorphine (t~/2 11 and 25 min vs 7 and 16 min respectively). In all the other patients there was monophasic elimination, gov-

erned by the slower rates of absorption and formation. Morphine was found in the serum 5 min after i. m. administration. The slow and individual absorption of nicomorphine from the muscle depot was followed by rapid formation of 6-MNM and morphine, which were eliminated with similar half-lives to the rate-limiting absorption halflife of nicomorphine. This situation does not differ much from the kinetic behavior after intravenous administration, because the tv2 of morphine is much longer (90200 min) than that of nicomorphine, even with slow absorption [1]. The inverse relationship between the A U C s of nicomorphine and morphine m a y have arisen because morphine may be formed from nicomorphine (r = ~).62) via 3-mononicotinoylmorphine. The glucuronide conjugates of 6-nicotinoylmorphine and morphine were not measured. Morphine is glucuronidated at the 3- and 6-positions, and 6-mononicotinoylmorphine at the 3-position. The glucuronide conjugates are excreted in the urine [3, 4, 5, 6]. The terminal serum halflife of morphine as metabolites varies between 40 and 100 rain, as reported for morphine as parent drug in the literature [3, 4, 5, 6, 7, 8]. Variation in the metabolic and absorption processes is reflected as variation in the A U C s of the unconjugated parent drug and unconjugated metabolites, as shown in Table 1. Nicomorphine and 6-nicotinoylmorphine had significantly higher A U C s after intramuscular than after intravenous injection, while the A U C s of morphine and the total A U C showed no difference between the two modes of administration. Like the analgesic effect of morphine-

378 6-glucuronide [9, 10], morphine-6-nicotinoate must also possess analgesic activity [11]. Depending on the purpose of nicomorphine administration, there is a choice between i. v. and i. m. administration. For long-lasting pain relief i.m. administration m a y be advantageous in the majority of patients (because of slower absorption). However, in some patients absorption is relatively rapid, the duration of action shorter and the absorption pattern cannot be predicted. The implications and mechanism of the slower absorption and longer disposition of nicomorphine and its active metabolites requires further investigation. In conclusion, because of the relatively slow absorption of nicomorphine from muscle after its i.m. injection the metabolites with analgesic activity, namely 6-nicotinoylmorphine and morphine, are present in the body for longer than after i. v. administration.

References

1. Koopman-Kimenai PM, Vree TB, Booij LHDJ, Dirksen R, Nijhuis GMM (1991) Pharmacokinetics of intravenously administered nicomorphine and its metabolites in man. Eur J Anaesthesiol (in press) 2. Koopman-Kimenai PM, Vree TB, Cress-Tijhuis MW, Booij LHDJ, Drijkoningen GJA (1987) High performance liquid chromatography and preliminary pharmacokinetics of nicomorfine and its metabolites 3-nicotinoyl- and 6-nicotinoylmorfine and morfine. J Chromatogr Biomed App1416:382-387

P. M. Koopman-Kimenai et al.: Nicomorphine kinetics

3. Boerner U, Abbott S, Roe RL (1985) The metabolism of morphine and heroin in man. Drug Metab Rev 4:39-73 4. Hug CC, Murphy MR, Rigel ER Olson WA (1981) Pharmacokinetics of morphine injected intravenously into the anesthetized dog. Anesthesiology 54:38-47 5. Sfiwe J, Dahlstr6m B, Paalzow L, Rane A (1981) Morphine kinetics in cancer patients. Clin Pharmacol Ther 30:629-635 6. S~iweJ, Kager L, Svensson J-O, Rane A (1985) Oral morphine in cancer patients: in vivo kinetics and in vitro hepatic glucuronidation. Br J Clin Pharmaco119: 495-501 7. Nordberg G, Borg L, Hedner T, Mellstrand T (1985) CSF and plasma pharmacokinetics of intramuscular morphine. Eur J Clin Pharmaco127:677-681 8. Stanski DR, Greenblatt D J, Lappas DG, Koch-Weser J, Lowenstein E (1976) Kinetics of high-dose intravenous morphine in cardiac surgery patients. Clin Pharmacol Ther 19:753-756 9. Osborne R, Joel S, Trew D, Slevin M (1990) Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine 6-O-glucuronide. Clin Pharmacol Ther 47:12-19 10. Shimomura K, Kamata O, Ueki S, Ida S, Oguri K, Yoshimura H, Tsukamoto H (1971) Analgesic effect of morphine glucuronides. Tohoku J Exp Med 105:45-52 11. Thorpe DH (1984) Opiate structure and activity. A guide to understanding the receptor. Anesth Analg 63:143-151

Dr. T. B. Vree Department of Clinical Pharmacy Geert Grooteplein Zuid 8 NL-6525 GA Nijmegen The Netherlands