Oral morphine in cancer patients: in vivo kinetics and in vitro hepatic glucuronidation.

Abstract

Sweden1 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. 2 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. 3 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 cleararnce between 18.6 and 34.0 ml min-' kg-1. This variation correlated with the variation in morphine metabolism as assessed in vitro. 4 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.

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

“…An initial PBPK model was developed using morphine‐specific physicochemical parameters and in vitro and in vivo data, as summarized in Table 1 4, 5, 6, 14, 15, 16, 17, 18. Morphine was assumed to be transported into hepatocytes via passive diffusion and OCT1 transporter‐mediated uptake.…”

“…After these estimated parameters for the hepatic uptake transport component were implemented into the model, the PK simulation of morphine was conducted using the same trial design as used for the parameter estimation process ( Supplementary Table S1 ). The simulation result of the morphine concentration‐time profiles are shown in Figure 1 a 17, 18, 23, 24, 25, 26 together with observed clinical data from six individual adult subjects. The predicted AUC ∞ and CL estimates were 49.4 ± 10 ng/mL*hr and 17.7 ± 3.8 mL/min/kg, respectively (mean ± SD; Table 3, 18, 25).…”

“…In this study, the relevant physicochemical parameters, in vitro , and in vivo data of morphine were collected from the literature. The morphine‐specific data collected are summarized in Table 1 4, 5, 6, 14, 15, 16, 17, 18. The morphine compound file was developed and validated in the adult Simcyp Simulator model (consisting of adult systems parameters) before being used in the Pediatric Simcyp Simulator model, which considers age‐dependent anatomic and physiological changes.…”

“…The maximum uptake rate for morphine transport in hepatocytes (J max , pmol/min/million hepatocytes) estimates, for each OCT1 genotype, was defined as the mean of J max ' (pmol/min/mg lysate protein) of the OCT1 variants in the OCT1‐overexpression cell system, as shown in Table 1 4, 5, 6, 14, 15, 16, 17, 18. For example, the J max ' estimate for OCT1*1/*2 was calculated as the mean of J max ' of *1 variant (29 pmol/min/mg lysate protein) and J max *2 variant (7.21 pmol/min/mg lysate protein); (29.0 + 7.21)/2 = 18.1 pmol/min/mg lysate protein, as summarized in Table 2 6.…”

“…A comprehensive PG study found that diplotypes containing haplotype #4 in UGT2B7 resulted in a significant increase in the formation of morphine 3 and 6‐glucuronidation (45% and 56%, respectively) compared with diplotypes without the haplotype #4 34. Based on the observed activity changes as a result of UGT2B7 genetic variants, the maximum velocity of UGT2B7‐mediated morphine glucuronidation in human liver microsomes was scaled from 50–150% of the default value (set at 100%), as shown in Table 1, 4, 5, 6, 14, 15, 16, 17, 18 for the simulations in virtual pediatric and adult healthy subjects.…”