How is Dilaudid (hydromorphone) metabolized?

From the Guidelines

Dilaudid (hydromorphone) is primarily metabolized in the liver through glucuronidation, which is the main pathway for its breakdown in the body, involving the enzyme UDP-glucuronosyltransferase to convert hydromorphone into hydromorphone-3-glucuronide, the major metabolite, as reported in the 2022 KLCA-NCC Korea practice guidelines for HCC 1.

Metabolism Pathway

The metabolism of hydromorphone involves:

• Glucuronidation: The primary pathway for hydromorphone metabolism, resulting in the formation of hydromorphone-3-glucuronide.
• Limited cytochrome P450 enzyme system involvement: Unlike some other opioids, hydromorphone does not undergo significant metabolism through this system.
• Conversion to dihydromorphine: A small amount of the drug is also converted to this metabolite.

Excretion

After metabolism, the metabolites of hydromorphone are:

• Primarily excreted through the kidneys in the urine.
• A small portion is eliminated in the feces.

Clinical Implications

The metabolism profile of hydromorphone is important clinically because:

• Patients with liver impairment may experience increased or prolonged effects from standard doses, requiring dose adjustments, as the metabolizing capacity of conjugating enzymes may be decreased in patients with hepatorenal syndrome due to accumulation of the neuroexcitatory metabolite 1.
• Patients with kidney dysfunction may have delayed clearance of metabolites, potentially leading to accumulation and increased side effects.

Key Considerations

• The half-life of hydromorphone is relatively short, approximately 2-3 hours, which explains its shorter duration of action compared to some other opioids.
• A reduction of dose with standard interval may be necessary in patients with hepatorenal syndrome, and it should be avoided in certain cases, as suggested in the guidelines 1.

From the FDA Drug Label

Hydromorphone is extensively metabolized via glucuronidation in the liver, with greater than 95% of the dose metabolized to hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites.

Metabolism of Dilaudid (Hydromorphone):

• Dilaudid (hydromorphone) is extensively metabolized in the liver.
• The primary metabolic pathway is glucuronidation, resulting in the formation of hydromorphone-3-glucuronide.
• Minor amounts of 6-hydroxy reduction metabolites are also produced.
• More than 95% of the dose is metabolized to hydromorphone-3-glucuronide 2.

From the Research

Metabolism of Dilaudid (Hydromorphone)

• Dilaudid, also known as hydromorphone, is metabolized by the liver to hydromorphone-3-glucuronide (H3G) 3, 4, 5, 6, 7
• H3G is a compound that can potentially cause neuroexcitatory phenomena with accumulation 3, 4, 5, 6
• The metabolism of hydromorphone to H3G occurs primarily through conjugation with glucuronic acid 5, 6, 7
• The steady-state molar ratio of H3G to hydromorphone is approximately 27:1, indicating that hydromorphone is extensively metabolized to H3G 7

Factors Affecting Metabolism

• Renal insufficiency can lead to increased levels of H3G, as it is primarily excreted by the kidneys 3
• The dose and duration of hydromorphone administration can also affect the levels of H3G, with higher doses and longer durations leading to increased accumulation of H3G 3, 4
• The pharmacokinetics of hydromorphone and H3G can vary between individuals, and may be affected by factors such as liver function and renal function 7

Neuroexcitatory Effects of H3G

• H3G has been shown to evoke neuroexcitatory effects, including myoclonus, allodynia, and seizures, in animal studies 4, 5, 6
• The potency of H3G in producing neuroexcitatory effects is approximately 2.5-fold greater than that of morphine-3-glucuronide (M3G) 6
• The accumulation of H3G in the central nervous system is thought to be responsible for the neuroexcitatory effects observed in some patients receiving chronic hydromorphone therapy 3, 4