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Data on drug transfer into human breast milk are sparse. This study aimed to quantify concentrations of cetirizine and levocetirizine in breast milk and to estimate drug exposure to infants. Breastfeeding women at least 8 weeks postpartum and using cetirizine or its pure (R)-enantiomer levocetirizine were eligible to participate. Breast milk samples were collected at six predefined times during a dose interval (0, 2, 4, 8, 12 and 24 h after drug intake) at steady state. Infant drug exposure was estimated by calculating the absolute infant dose (AID) and the weight-adjusted relative infant dose (RID). In total, 32 women were eligible for final inclusion, 31 women using cetirizine and one woman using levocetirizine. Means of the individual maximum and average cetirizine milk concentrations were 41.0 and 16.8 μg/L, respectively. Maximum concentrations occurred on average 2.4 h after intake, and the mean half-life in milk was 7.0 h. Estimated AID and RID for cetirizine in a day were 2.5 μg/kg and 1.9%, respectively. The corresponding values for levocetirizine were 1.1 μg/kg and 1.9%. No severe adverse events were reported. Our findings demonstrate that the transfer of cetirizine and levocetirizine into breast milk is low and compatible with breastfeeding., (© 2023 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Rosuvastatin is a frequently used probe to study transporter-mediated hepatic uptake. Pharmacokinetic models have therefore been developed to predict transporter impact on rosuvastatin disposition in vivo. However, the interindividual differences in transporter concentrations were not considered in these models, and the predicted transporter impact was compared with historical in vivo data. In this study, we investigated the influence of interindividual transporter concentrations on the hepatic uptake clearance of rosuvastatin in 54 patients covering a wide range of body weight. The 54 patients were given an oral dose of rosuvastatin the day before undergoing gastric bypass or cholecystectomy, and pharmacokinetic (PK) parameters were established from each patient's individual time-concentration profiles. Liver biopsies were sampled from each patient and their individual hepatic transporter concentrations were quantified. We combined the transporter concentrations with in vitro uptake kinetics determined in HEK293-transfected cells, and developed a semimechanistic model with a bottom-up approach to predict the plasma concentration profiles of the single dose of rosuvastatin in each patient. The predicted PK parameters were evaluated against the measured in vivo plasma PKs from the same 54 patients. The developed model predicted the rosuvastatin PKs within two-fold error for rosuvastatin area under the plasma concentration versus time curve (AUC; 78% of the patients; average fold error (AFE): 0.96), peak plasma concentration (C max ; 76%; AFE: 1.05), and terminal half-life (t 1/2 ; 98%; AFE: 0.89), and captured differences in the rosuvastatin PKs in patients with the OATP1B1 521T

The liver and small intestine restrict oral bioavailability of drugs and constitute the main sites of pharmacokinetic drug-drug interactions. Hence, detailed data on hepatic and intestinal activities of drug metabolizing enzymes is important for modeling drug disposition and optimizing pharmacotherapy in different patient populations. The aim of this study was to determine the activities of seven cytochrome P450 (P450) enzymes in paired liver and small intestinal samples from patients with obesity. Biopsies were obtained from 20 patients who underwent Roux-en-Y gastric bypass surgery following a 3-week low-energy diet. Individual hepatic and intestinal microsomes were prepared and specific probe substrates in combined incubations were used for determination of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A activities. The activities of CYP2C8, CYP2C9, CYP2D6, and CYP3A were quantified in both human liver microsomes (HLM) and human intestinal microsomes (HIM), while the activities of CYP1A2, CYP2B6, and CYP2C19 were only quantifiable in HLM. Considerable interindividual variability was present in both HLM (9- to 23-fold) and HIM (5- to 55-fold). The median metabolic HLM/HIM ratios varied from 1.5 for CYP3A to 252 for CYP2C8. The activities of CYP2C9 in paired HLM and HIM were positively correlated ( r = 0.74, P < 0.001), while no interorgan correlations were found for activities of CYP2C8, CYP2D6, and CYP3A ( P > 0.05). Small intestinal CYP3A activities were higher in females compared with males ( P < 0.05). Hepatic CYP2B6 activity correlated negatively with body mass index ( r = -0.72, P < 0.001). These data may be useful for further in vitro-in vivo predictions of drug disposition in patients with obesity. SIGNIFICANCE STATEMENT: Hepatic and intestinal drug metabolism is the key determinant of oral drug bioavailability. In this study, paired liver and jejunum samples were obtained from 20 patients with obesity undergoing gastric bypass surgery following a 3-week low-energy diet. We determined the hepatic and small intestinal activities of clinically important P450 enzymes and provide detailed enzyme kinetic data relevant for predicting in vivo disposition of P450 substrates in this patient population., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)