Medicinal Chemistry Topic:

Medicinal Chemistry of Opioid Analgesics (Part 2)

We’ve already talked about the medicinal chemistry of opioid analgesics, with a strong focus on morphine. Here, we talk more about the pharmacokinetics of morphine and other, structurally similar opioids.

Pharmacokinetics of Morphine

Possible routes of administration for morphine include:

  • Oral
  • Sublingual
  • Buccal
  • Rectal
  • Subcutaneous
  • Intranasal
  • Intravenous (most common for medical purposes)
  • Intrathecal
  • Epidural
  • Inhaled (via a nebulizer)

The oral route of administration is most convenient for patients. Morphine readily undergoes first-pass metabolism when taken orally, with only a relatively low percentage of the drug traversing the blood-brain barrier (BBB), reaching target opioid receptors. For this reason,to achieve a similar level of analgesia as parenterally administered morphine, oral doses tend to be six times larger.

The absorption, metabolism and excretion of morphine are summarised below.


Orally administered morphine, which has a basic moiety, is readily absorbed in the alkaline environment of the upper intestine.


  1. Glucoronidation:

In mammals, a bioconjugation reaction known as glucuronidation, facilitated by UDP-glucuronosyltransferase (UGT) enzymes in the liver, is the main metabolic reaction of morphine, with glucuronidation occurring at the hydroxyl groups at positions 3 and 6. Glucuronidation at positions 3 and 6 give the following metabolites:

  • 3: Morphine-3-glucuronide = not active as an opioid agonist
  • 6:Morphine-6-glucuronide (M6G) = an active metabolite of morphine

Revision Questions:

Q1) Are glucuronidation reactions Phase I or Phase II metabolism reactions?

Q2) Would you expect the glucuronidated metabolites to readily cross the blood-brain barrier?

  1. N-demethylation:

The tertiary amine group can undergo an N-demethylation (catalysed by cytochrome P450 3A4 [CYP3A4] and cytochrome P450 2C8 [CYP2C8]) to give the N-demethylated metabolite with a secondary amine, normorphine. Normorphine is more polar than morphine due to the -NH group and for this reason, normorphine’s ability to cross the blood-brain barrier is lower. Thus, normorphine is a weaker analgesic than morphine.


Metabolism rates and efficiency depend on factors such as the gender, age, diet and genetic makeup of the patient. In the case of morphine, which is mainly excreted via urine, 70-80% of a dose of morphine is excreted after 48 h from administration.

Answers to Revision Questions

Q1) Phase II, which are bioconjugation reactions

Q2) The glucuronidated metabolites have increased polar character due to the introduction of a moiety with several polar groups (hydroxyls and a carboxylic acid). For this reason, the glucuronidated metabolites are less lipophilic and therefore less able to cross the blood-brain barrier.

Pharmacokinetics of Codeine

The key structural difference between codeine and morphine is at position 3, where in the case of codeine, position 3 has an –OMe methyl ether group.

On the other hand, morphine has a hydroxyl group. Codeine can be thought of as a prodrug of morphine since an O-demethylation metabolism reaction takes place to give morphine, which undergoes many of the biotransformations described above.

Like morphine, the –OH group at position 6 of codeine can undergo glucuronidation to give codeine-6-glucuronide (catalysed by CYP2D6). Since there is no free hydroxyl group in the case of codeine, glucuronidation cannot occur at position 3. Codeine can also undergo Ndemethylation to give norcodeine (catalysed by CYP3A4). Approximately 90% of the total dose of codeine is excreted by the kidneys.

Pharmacokinetics of Naloxone

Like we talked about with other opioids, the opioid antagonist naloxone primarily undergoes hepatic metabolism, with a urine-excreted glucuronide metabolite (naloxone-3-glucuronide) as its main metabolite.

Further Reading

  1. Stein, C. Opioid Receptors. Annu. Rev. Med. 2016, 67 (1), 433–451 DOI: 10.1146/annurev-med-062613-093100.
  2. Del Vecchio, G.; Spahn, V.; Stein, C. ACS Chem. Neurosci. 2017, 8 (8), 1638–1640. DOI: 10.1021/acschemneuro.7b00195
  3. Patrick, G. L. An Introduction to Medicinal Chemistry 2013.
  4. Graziottin, A.; Gardner-Nix, J.; Stumpf, M.; Ber
  5. De Gregori, S.; De Gregori, M.; Ranzani, G. N.; Allegri, M.; Minella, C.; Regazzi, M. Metab. Brain Dis. 2012, 27 (1), 1–5 DOI: 10.1007/s11011-011-9274-6.