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History: people used to think glucourinides are completely inactive, end of story

But with morphine, M-6-G is active (3 isnt)

Problem is with the dosing, because M-6-G will accumulate

Another thing to recognise is to make sure their bile system works, due to enterohepatic recycling

M6G or the 3 can be broken back down into morphine and reabsorbed

What is the aim of the study?

M-6-G is a potent and long lasting metabolite, which has analgesic activityo More potent and less side effects compared to morphineo Has greater affinity to the mu-1 receptor (associated with analgesia) compared to

the mu-2 receptor, which is associated with nausea and respiratory depression

Most chronic pain is managed through oral morphine and s.c. morphine for people unable totake it par orally (p.o. or just orally)

o Evidence suggests nebulised forms might work as well Therefore, testing M-6-G via i.v., s.c., p.o. or nebulised

Trial method Subjects

o Ethics committee specified the volunteers can only receive 6 life time doses due toconcerns over addiction; also cannot be students or pre-registration house staff or

secretarial staff due to possible cohersion

o Made sure they were healthy prior to starting, and were not taking other drugs ofabuse

o 10 people were recruitedo 4-way crossover, randomised order

2mg i.v. 2mg s.c. 20mg p.o. 4mg nebulised

Fasting (important because of enerohepatic recirculation)o Fasted over nighto Nil-by-mouth (no water or food) for 4 hours

Supine for the first 2 hours 1 week washout

o Maybe wasnt long enough for oralIntravenous (control)

2mg Half life of 1.7h

o Fastest half-life Cmax = 539 nmol.l-1

o Highest Cmax 100% bioavailability MRT of 1.8h

o Shortest MRT Most changes in nausea, sedation mood and dysphoria

Oral

20mg, highest dose (2mg iv sc, 4pm nebulised) Half-life not measurable, two peaks detected as well

o Little drop in concentration over time

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o AUC not properly measurableo This is typical of enterohepatic recycling

Cmax = 42 nmol.l-1 11% bioavailability

o Total guess because the AUC isnt properly measurable MRT of 11.5 hours, significantly longer than i.v. Very interesting effects at 4h

o This is when they got foodo M-6-G stored in bile, released with eatingo Leads to increase in M-3-G and morphine after 4h due to morphine/M-6-G being

reabsorbed via enterohepatic recycling (Figure 4)

Only came from p.o. route Must have come from M-6-G being hydrolysed by gut bacteria into

morphine

Morphine is absorbed, which can be detected, and be metabolised into M-3-G

Note: 2x M-3-G produced compared to M-6-G from morphine, which can beseen from high M-3-G levels buto M-6-G is still present at quite high levels after 24 hours (Figure 4) which suggests

its still being absorbed as itself

o Also leads to the second peak in p.o. route (Figure 1) Overall, its better for a person to take morphine orally, because you get M-6-G from oral

morphine anyway.

o Therefore, M-6-G is best taken either i.v. or s.c. (s.c. is especially important foroncology patients for breakthrough pain, because they cant use the i.v. route as its

already in use.M-

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Subcutaneous

2mg Half-life of 1.9h

o Comparable to i.v. (1.7h) Cmax = 207 nmol.l-1

o About half of control 102% bioavailability

o Pretty much all availableo Assuming theres no drug left from previous dose (some may be possible from oral)

MRT of 2.2ho Significantly longer compared to i.v. (1.8h)o Because needs time to absorb

Good for systemic use, especially if the i.v. route is not availableNebulized

4mgo Double the dose from i.v. or s.c. (2mg)

Half-life of 3.1ho Significantly higher than control (1.7h)o Maybe under absorption controlled processes

Cmax = 11 nmol.l-1o Lowest Cmax of all routes

6% bioavailabilityo Even lower than oral (11%)

MRT of 4.9ho Significantly longer compared to control (1.8h)

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No good for systemic use, but may be good for local effects, like breathlessness (futurestudy)

Half life cmax bioavailability MRT, dose important