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Oral morphine in cancer patients: in vivo kinetics and in vitro hepatic glucuronidation
Abstract:
The kinetics of morphine and formation of the main metabolite, morphine-3-glucuronide (M3G) after single and intravenous doses of morphine were studied in six cancer patients and compared with the formation rate of M3G in vitro in microsomes isolated from liver biopsies obtained from the same patients at palliative laparotomy. The results showed that high formation rates of M3G in vitro in microsomes isolated from liver biopsies were associated both with high apparent oral clearance values and high M3G/morphine AUC (area under the concentration vs time curve) ratios as measured in vivo in the same patients. In accordance with previous results marked interindividual differences were seen in the kinetics of morphine; the oral bioavailability varied between 30 and 69% and the systemic plasma clearance between 18.6 and 34.0 ml min-1 kg-1. This variation correlated with the variation in morphine metabolism as assessed in vitro. In vivo, a high M3G/morphine AUC ratio predicted a high oral clearance. Hepatic UDP-glucuronyl transferase activity is thus an important determinant of the in vivo kinetics of orally administered morphine.
Insights
Morphine metabolism varies significantly between individuals. Higher in vitro morphine-3-glucuronide (M3G) formation in liver microsomes predicts faster in vivo morphine clearance and higher oral bioavailability.
Area of Science:
- Pharmacokinetics
- Drug Metabolism
- Hepatology
Background:
- Morphine is a key analgesic for cancer pain.
- Morphine-3-glucuronide (M3G) is its primary metabolite.
- Interindividual variability in morphine pharmacokinetics is well-documented.
Purpose of the Study:
- To investigate the relationship between in vitro M3G formation and in vivo morphine kinetics.
- To assess the role of hepatic UDP-glucuronyl transferase activity in morphine disposition.
Main Methods:
- Studied morphine and M3G pharmacokinetics in six cancer patients after IV doses.
- Measured in vitro M3G formation rates in liver microsomes from patient biopsies.
- Correlated in vitro metabolic rates with in vivo pharmacokinetic parameters (clearance, AUC, bioavailability).
Main Results:
- High in vitro M3G formation correlated with high in vivo oral clearance and M3G/morphine AUC ratios.
- Significant interindividual differences observed in morphine oral bioavailability (30-69%) and plasma clearance (18.6-34.0 ml min-1 kg-1).
- In vivo M3G/morphine AUC ratio predicted higher oral clearance.
Conclusions:
- Hepatic UDP-glucuronyl transferase activity is a crucial determinant of oral morphine pharmacokinetics.
- In vitro assays can predict in vivo morphine metabolism and disposition.
- Understanding these variations is vital for optimizing morphine therapy in cancer patients.