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This study aims to evaluate the impact of liver fibrosis stages of chronic infection with hepatitis C virus (HCV) on the in vivo activity of organic cation transporters (hepatic OCT1 and renal OCT2) using metformin (MET) as a probe drug. Participants allocated in Group 1 (n = 15, mild to moderate liver fibrosis) or 2 (n = 13, advanced liver fibrosis and cirrhosis) received a single MET 50 mg oral dose before direct-acting antiviral (DAA) drug treatment (Phase 1) and 30 days after achieving sustained virologic response (Phase 2). OCT1/2 activity (MET AUC0–24) was found to be reduced by 25% when comparing the two groups in Phase 2 (ratio 0.75 (0.61–0.93), p < 0.05) but not in Phase 1 (ratio 0.81 (0.66–0.98), p > 0.05). When Phases 1 and 2 were compared, no changes were detected in both Groups 1 (ratio 1.10 (0.97–1.24), p > 0.05) and 2 (ratio 1.03 (0.94–1.12), p > 0.05). So, this study shows a reduction of approximately 25% in the in vivo activity of OCT1/2 in participants with advanced liver fibrosis and cirrhosis after achieving sustained virologic response and highlights that OCT1/2 in vivo activity depends on the liver fibrosis stage of chronic HCV infection. [ABSTRACT FROM AUTHOR]

This work aimed to evaluate the total, unbound, renal, and hepatic clearances of raltegravir (RAL) and the formation and elimination clearances of raltegravir glucuronide (RAL GLU) in pregnant women living with HIV. The participants received RAL 400 mg twice daily during the third trimester (n = 15) of gestation, delivery (n = 15), and the postpartum period (n = 8). Pharmacokinetic parameter values were calculated on the basis of plasma and urine data using noncompartmental methods. RAL clearances for the third trimester of gestation were as follows: total clearance: geometric mean, 63.63 L/h (95% CI, 47.5–85.25); renal clearance: geometric mean, 2.56 L/h (95% CI, 1.96–3.34); hepatic clearance: geometric mean, 60.52 L/h (95% CI, 44.65–82.04); and unbound clearance: geometric mean, 281.14 L/h (95% CI, 203.68–388.05). RAL GLU formation and elimination clearances for the third trimester of gestation were 7.57 L/h (95% CI, 4.94–11.6) and 8.71 L/h (95% CI, 6.71‐11.32), respectively. No differences were observed in RAL GLU pharmacokinetic parameters between the third trimester of gestation and the postpartum period, except for higher formation (7.57 vs 4.03 L/h) and elimination (8.71 vs 4.92 L/h) clearances during the third trimester. The findings based on plasma and urine data are consistent with an increase in the hepatic uridine 5′ diphospho‐glucuronosyltransferase isoenzymes activities involved in RAL metabolism during pregnancy, and the formation of RAL GLU is a minor route of RAL elimination. Compared to the postpartum period, in the third trimester of gestation, the similar RAL plasma exposure in pregnant women reinforces the maintenance of an RAL regimen including a 400‐mg oral dose twice daily during pregnancy. [ABSTRACT FROM AUTHOR]

The activity of the membrane transporters organic anion‐transporting polypeptide 1B1 (OATP1B1) & breast cancer resistance protein (BCRP) (rosuvastatin) and P‐glycoprotein (P‐gp) (fexofenadine) was evaluated in patients with chronic hepatitis C virus (HCV) infection (n = 28), genotypes 1 and 3, investigated before the treatment with direct‐acting antiviral agents (Phase 1) and up to 30 days after the assessment of the virologic response (Phase 2). Participants allocated in Groups 1 (n = 15; F0/F1 and F2, mild to moderate liver fibrosis) and 2 (n = 13; F3 and F4, advanced course of liver fibrosis/cirrhosis) received in both phases fexofenadine (10 mg) and rosuvastatin (2 mg). OATP1B1 & BCRP activity (rosuvastatin area under the plasma concentration‐time curve of rosuvastatin from time zero to infinity (AUC0–∞)) was reduced in Groups 1 and 2, respectively, by 25% (ratio 0.75 (0.53–0.82), P < 0.01) and 31% (ratio 0.69 (0.46–0.85), P < 0.05) in Phase 1 compared with Phase 2. OATP1B1 & BCRP activity was reduced in Phases 1 and 2, respectively, by 49% (median ratio 1.51 (1.17–2.20), P < 0.05) and 61% (ratio 1.39 (1.16–2.02), P < 0.01) in Group 2 compared with Group 1. P‐gp activity (fexofenadine AUC0–∞) was also reduced in Phase 1 compared with Phase 2 (ratio Phase2/Phase1 0.79 (0.66–0.96) in Group 1 and 0.81 (0.69–0.96) in Group 2) as well as in Group 2 compared with Group 1 in both Phases (ratio Group2/Group1 1.47 (1.08–2.01) in Phase 1 and 1.51 (1.10–2.07) in Phase 2). Thus, clinicians administering OATP1B1 & BCRP and P‐gp substrates with low therapeutic indexes should consider the evolution of the treatment and the stage of HCV infection. [ABSTRACT FROM AUTHOR]

This study evaluates the influence of streptozotocin-induced diabetes on the kinetic disposition and metabolism of mexiletine (MEX) enantiomers in rats. Animals in the control (n = 6 for each blood collection time), diabetic (single intravenous dosage of 45 mg x [(kg body mass).sup.-1] of streptozotocin), and insulin-treated groups (diabetic rats treated daily with 2 IU insulin) received by gavage a single dose of 10 mg x [(kg body mass).sup.-1] racemic MEX. MEX enantiomers and the metabolites hydroxymethylmexiletine (HMM) and p-hydroxymexiletine PHM) were analyzed by LC-MS/MS. Statistical analysis was based on a serial sacrifice design, and parameter estimation was performed using a Bayesian modeling procedure. Area under the curve (AUC) for the (-)-(R) enantiomers of MEX, HMM, and PHM did not differ between the control and diabetic groups. However, AUC for (+)-(S)-MEX and (+)-(S)-HMM were lower in the diabetic than in the control group. Insulin treatment recovered glucose levels to normal and the (+)-(S)-MEX AUC and (+)-(S)-HMM AUC became similar to the AUCs observed in the nondiabetic animals. Key words: mexiletine, enantiomers, metabolites, pharmacokinetics, diabetes, insulin, rats. Cette etude evalue l'influence du diabete induit par la streptozotocine sur la disposition cinetique et le metabolisme des enantiomeres de la mexiletine (MEX) chez le rat. Les animaux des groupes controle (n = 6a chaque prelevement sanguin), diabetique (une seule dose i.v. de 45 mg x [(kg de masse corporelle).sup.-1] de streptozotocine) et traite a l'insuline (diabetique traite quotidiennement avec 2 UI d'insuline) ont recu par gavage une seule dose de 10 mg x [(kg de masse corporelle).sup.-1] d'un melange racemique de MEX. Les enantiomeres de MEX et leurs metabolites, la hydroxymethylmexiletine (HMM) et la p-hydroxymexiletine (PHM), ont ete analyses par LC-MS/MS. L'analyse statistique a ete basee sur des donnees issues d'un protocole de sacrifice seriel et l'estimation parametrique a ete realisee par une modelisation Bayesienne. Les aires sous la courbe (ASC) des enantiomeres (-)-(R) de MEX, de HMM et de PHM ne differaient pas significativement entre les groupes controle et diabetique. Toutefois les ASC de (+)-(S)-MEX et (+)-(S)-HMM etaient plus faibles chez le groupe diabetique comparativement au groupe controle. Le traitement a l'insuline permettait de retablir les niveaux normaux de glucose et les ASC de (+)-(S)-MEX et de (+)-(S)-HMM similaires a ceux des animaux non diabetiques. [Traduit par la Redaction] Mots-cles: mexiletine, enantiomeres, metabolites, pharmacocinetique, diabete, insuline, rats., Introduction Mexiletine (MEX; 1-(2,6-dimethylfenoxi)-2-aminopropane), a drug available as a racemic mixture of (-)-R and (+)-(S) enantiomers, is used clinically for alleviating neuropathic pain in diabetes (Andriaensen et al. 2005). The [...]