ABSTRACT
Altered expression and function of transporters in nonalcoholic steatohepatitis (NASH) patients may affect the pharmacokinetics (PK), efficacy, and safety of substrate drugs. A population pharmacokinetic (PopPK) analysis was performed to assess differences in morphine and morphine-3-glucuronide (M3G) disposition in NASH and healthy subjects. A total of 315 serum and 42 urine samples from 21 subjects (14 healthy; 7 NASH) were analyzed using NONMEM. Morphine and M3G PK were described by three- and one-compartment models, respectively. After accounting for the effect of total body weight on all clearance and volume of distribution parameters using an allometric scaling approach, NASH severity score (NASF; combination of fibrosis and nonalcoholic fatty liver disease activity scores) was the most significant predictor of differences in M3G exposure. The model predicted a linear decrease in the clearance of M3G with increasing NASF scores on a natural logarithmic scale. These results may provide some insight into the potential effect of NASH on the disposition of hepatic transporter substrates.
Subject(s)
Analgesics, Opioid/pharmacokinetics , Models, Biological , Morphine Derivatives/metabolism , Morphine/pharmacokinetics , Non-alcoholic Fatty Liver Disease/metabolism , Adult , Analgesics, Opioid/blood , Analgesics, Opioid/urine , Female , Healthy Volunteers , Humans , Male , Middle Aged , Morphine/blood , Morphine/urine , Non-alcoholic Fatty Liver Disease/blood , Non-alcoholic Fatty Liver Disease/urine , Tissue Distribution , Young AdultABSTRACT
The functional impact of altered drug transport protein expression on the systemic pharmacokinetics of morphine, hepatically derived morphine glucuronide (morphine-3- and morphine-6-glucuronide), and fasting bile acids was evaluated in patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) compared to healthy subjects. The maximum concentration (Cmax ) and area under the concentration-time curve (AUC0-last ) of morphine glucuronide in serum were increased in NASH patients (343 vs. 225 nM and 58.8 vs. 37.2 µM*min, respectively; P ≤ 0.005); morphine pharmacokinetics did not differ between groups. Linear regression analyses detected an association of NASH severity with increased morphine glucuronide Cmax and AUC0-last (P < 0.001). Fasting serum glycocholate, taurocholate, and total bile acid concentrations were associated with NASH severity (P < 0.006). Increased hepatic basolateral efflux of morphine glucuronide and bile acids is consistent with altered hepatic transport protein expression in patients with NASH and may partially explain differences in efficacy and/or toxicity of some highly transported anionic drugs/metabolites in this patient population.
Subject(s)
Analgesics, Opioid/metabolism , Bile Acids and Salts/metabolism , Morphine Derivatives/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Adult , Analgesics, Opioid/pharmacokinetics , Area Under Curve , Cohort Studies , Female , Humans , Insulin Resistance , Liver/metabolism , Liver/pathology , Liver Cirrhosis/metabolism , Male , Middle Aged , Morphine Derivatives/pharmacokinetics , Non-alcoholic Fatty Liver Disease/pathologyABSTRACT
We describe a simple, rapid procedure for the estimation of carbamazepine in plasma. Protein is precipitated, and extraction is achieved by the addition of acetonitrile containing the internal standard N-acetyltryptophan ethyl ester. Separation is by reverse-phase high-pressure liquid chromatography with an acetonitrile: water mobile phase, and detection is by UV absorption at 280 nm. Total retention time is less than 7 minutes. Initial results gave within-batch and between-batch coefficients of variation of less than 2%, and mean recovery of 97%. The method is free from interference by other common anticonvulsant drugs.
