Current Drug Metabolism - Volume 21, Issue 4, 2020

Background: Inflammatory bowel disease, including both Crohn’s disease and ulcerative colitis, are two chronic and progressive disorders affecting the gastrointestinal tract. Research on the molecular mechanisms of both diseases has led to the introduction of targeted therapies which are able to selectively block the key inflammatory mediators. Methods: Here, we discuss the current evidence about the mechanism of action with an up to date review of the efficacy and safety of Janus kinase inhibitors in inflammatory bowel disease. Results: Multiple small molecule drugs have been evaluated for their use in both ulcerative colitis and Crohn’s disease. Janus kinase inhibitors represent the most important family of these drugs, as their particular mechanism of action enables a simultaneous and effective blockade of multiple cytokines involved in the pathogenesis of the disease. Conclusion: Janus kinase inhibitors represent a promising therapeutic strategy, especially in ulcerative colitis. More data are still necessary regarding its efficacy and safety in clinical practice.

The liver represents the major site of drug metabolism, i.e. the key organ in the processes of detoxification and elimination of drugs from the organism. It is therefore often affected by toxic metabolites and suffers sometimes fatal consequences. The spectrum of pathologies differs by the cell type primarily damaged and the group of the cholangiopathies includes those conditions affecting the bile duct epithelium or the cholangiocytes. They can range from transient cholestasis to vanishing bile duct syndrome and sclerosing cholangitis, both leading eventually to the development of biliary fibrosis and cirrhosis. In this review article, we focus on the etiology, predisposing factors, clinical manifestations, and histopathological characteristics of bile duct injury as a consequence of drug treatment and discuss separately the different bile duct pathologies.

Among the gut microbiota’s newly explored roles in human biology is the ability to modify the chemical structures of foreign compounds (xenobiotics). A growing body of evidence has now provided sufficient acumen on the role of the gut microbiota on xenobiotic metabolism, which could have an intense impact on the therapy for various diseases in the future. Gut microbial xenobiotic metabolites have altered bioavailability, bioactivity and toxicity and can intervene with the actions of human xenobiotic-metabolizing enzymes to affect the destiny of other ingested molecules. These modifications are diverse and could lead to physiologically important consequences. In the current manuscript we aim to review the data currently available on how the gut microbiota directly modifies drugs, dietary compounds, chemicals, pollutants, pesticides and herbal supplements.

Background: Appropriate dosing of gentamicin in critically ill neonates is still debated. Objective: To assess the peak concentration (Cmax) and area-under-the-time-concentration curve (AUC0-24) of gentamicin and to simulate the recommended doses using the Monte Carlo method. Methods: This was a retrospective study on critically ill neonates carried over a one-year period. The demographic characteristics, dosage regimen and gentamicin concentrations were recorded for each neonate. Using Bayesian pharmacokinetic modeling, Cmax and AUC0-24 were predicted. Dose recommendations for the target Cmax (μg/ml) of 12 were obtained, and Monte Carlo simulation (100,000 iterations) was used for predicting the pharmacokinetic parameters and recommended doses for various birth weight categories. Results: Eighty-two critically ill neonates (with an average gestational age of 33.7 weeks; and birth weight of 2.1 kg) were recruited. Higher Cmax and AUC0-24 values were predicted in premature neonates, with greater cumulative AUCs in extremely preterm neonates. The average administered dose was 4 mg/kg/day and 75% of the participants had Cmax greater than 12 μg/ml following a single dose, and 85% were found to be at steady state. On the contrary, only 25% of the study population had the recommended AUC0-24 (above 125 μg-hr/ml). Simulation tests indicate that 90% of the critically ill neonates would achieve recommended Cmax with doses ranging between 5 and 6 mg/kg/day. Conclusion: Currently used dose of 4 mg/kg/day is adequate to maintain Cmax in a large majority of the study population, with one-fourth population reporting the recommended AUC0-24. Increasing the dose to 5-6 mg/kg/day will more likely help to achieve both the recommended Cmax and AUC0-24 values.

Background: Maytenus ilicifolia is a Brazilian popular medicine commonly used to treat ulcer and gastritis. Despite the absence of toxicity regarding its consumption, possible interactions when co-administrated with conventional drugs, are unknown. Objective: This study aimed to evaluate the effects of M. ilicifolia extracts on Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) activities. Methods: The extracts were obtained by infusion (MI) or turbo-extraction using hydro-acetonic solvent (MT70). The content of polyphenols in each extract was determined. To assess the modulation of M. ilicifolia on P-gp activity, the uptake of fexofenadine (FEX) by Caco-2 cells was investigated in the absence or presence of MI or MT70. The effect on CYP3A activity was evaluated by the co-administration of midazolam (MDZ) with each extract in male Wistar rats. The pharmacokinetic parameters of the drug were determined and compared with those from the control group. The content of total phenolic compounds, tannins, and flavonoids on MT70 extract was about double of that found in MI. Results: In the presence of the extracts, the uptake of the P-gp marker (FEX) by Caco-2 cells increased from 1.7 ± 0.4 ng.mg-1 protein (control) to 3.5 ± 0.2 ng.mg-1 protein (MI) and 4.4 ± 0.5 ng.mg-1 protein (MT70), respectively. When orally co-administrated with MDZ (substrate of CYP3A), the extracts augmented the AUC(0-∞) (Control: 911.7 ± 215.7 ng.h.mL-1; MI: 1947 ± 554.3 ng.h.mL-1; MT70: 2219.0 ± 506.3 ng.h.mL-1) and the Cmax (Control: 407.7 ± 90.4 ng.mL-1; MI: 1770.5 ± 764.5 ng.mL-1; MT70: 1987.2 ± 544.9 ng.mL-1) of the drug in rats indicating a 50% reduction of the oral Cl. No effect was observed when midazolam was given intravenously. Conclusion: The results suggest that M. ilicifolia can inhibit the intestinal metabolism and transport of drugs mediated by CYP3A and P-gp, respectively, however, the involvement of other transporters and the clinical relevance of such interaction still need to be clarified.

Background: In Mexico, approximately 25% of patients with type 2 diabetes (T2D) have adequate glycemic control. Polymorphisms in pharmacogenetic genes have been shown to have clinical consequences resulting in drug toxicity or therapeutic inefficacy. Objective: The study aimed to evaluate the impact of variants in genes known to be involved in response to oral hypoglycemic drugs, such as CYP2C9, OCT, MATE, ABCA1 and C11orf65, in the Mexican Mestizo population of T2D patients. Methods: In this study, 265 patients with T2D were enrolled from the Hospital Juárez de México, Mexico City. Genotyping was performed by TaqMan® assays. SNP-SNP interactions were analyzed using the multifactor dimensionality reduction (MDR) method. Results: Carriers of the del allele of rs72552763 could achieve better glycemic control than noncarriers. There was a significant difference in plasma glucose and HbA1c levels among rs622342 genotypes. The results suggested an SNP-SNP interaction between rs72552763 and rs622342 OCT1 and rs12943590 MATE2. Conclusion: The interaction between rs72552763 and rs622342 in OCT1, and rs12943590 in MATE2 suggested an important role of these polymorphisms in metformin response in T2D Mexican Mestizo population.

Background: Metoclopramide is metabolized by various cytochrome P450 (CYP) enzymes such as CYP3A4, CYP1A2, CYP2D6, CYP2C9, and CYP2C19. Rifampicin is a non-selective inducer of P-glycoprotein (P-gp) and CYP enzymes such as CYP3A4 and others. Objective: This study was aimed at the evaluation of rifampicin’s enzyme induction effect on the pharmacokinetic parameters of orally administered metoclopramide. Method: This randomized, single-blind, two-phase cross-over pharmacokinetic study separated by a 4-week washout period was conducted at a single center in Pakistan. It involved twelve Pakistani healthy male volunteers (nonsmokers) divided into two groups. In the reference phase, each volunteer received a single oral dose of 20 mg metoclopramide (Maxolon 10 mg, GlaxoSmithKline, Pakistan), while in the rifampicin-treated phase, each volunteer received 600 mg rifampicin once daily for 6 days through oral route. On day 6, metoclopramide (20 mg) was administered 2 hours after the last pretreatment dose of rifampicin. The serial blood samples were collected on predetermined time points (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 18 h) and analyzed using a validated HPLC method for the determination of pharmacokinetic parameters, i.e. Cmax, Tmax, and AUC0-∞ of metoclopramide. The whole study was monitored by an unblinded clinician for the purpose of volunteer’s health safety. Results: All the volunteers participated in the study until the end. Twelve healthy Pakistani males having mean age 26.0 (range 20.6-34.1) years and body mass index 25.1 (range 16.2-31.5) kg/m2 were included in this study after taking written informed consent. Rifampicin significantly (P<0.05) decreased the mean Cmax, AUC0-∞ and T1/2 of metoclopramide by 35%, 68%, and 44%, respectively. The laboratory tests did not reveal any significant change in the biochemical, physical, hematological, or urinalytical values before and after metoclopramide treatment. None of the volunteers complained of any discomfort during the study. Conclusion: Rifampicin noticeably decreased the concentration of plasma metoclopramide. These results give in vivo confirmation of the CYP3A4 involvement in the metoclopramide metabolism, in addition to CYP2D6. Therefore, metoclopramide pharmacokinetics may be clinically affected by rifampicin and other potent enzyme inducers.

Background: Differences in individual responses to the same medications remarkably differ among populations. A number of genes that play integral roles in drug responses have been designated as very important pharmacogenes (VIP), as they are responsible for differences in drug safety, efficacy, and adverse drug reactions among certain ethnic groups. Identifying the polymorphic distribution of VIP in a range of ethnic groups will be conducive to population-based personalized medicine. Objective: The aim of the current study is to identify the polymorphic distribution of VIP regarding the Chechen minority group from Jordan and compare their allele frequencies with other populations. Methods: A total of 131 unrelated Chechen individuals from Jordan were randomly recruited for blood collection. Identification of allelic and genotypic frequencies of eleven VIP variants within the genes of interest (ABCB1, VDR and TPMT) was carried out by means of the MassARRAY®System (iPLEX GOLD). Results: Within ABCB1, we found that the minor allele frequencies of the rs1128503 (A: 0.43), rs2032582 (A: 0.43), rs1045642 (A: 0.43). For VDR, the minor allele frequencies of rs11568820 (T: 0.18), rs1540339 (T: 0.30), rs1544410 (T: 0.41), rs2228570 (T: 0.24), rs3782905 (C: 0.28) and rs7975232 (C: 0.45). Finally, the minor allele frequencies for the TPMT rs1142345 and rs1800460 polymorphisms were found to be (C: 0.02) and (T: 0.01), respectively. Conclusion: Significant differences in allelic frequencies of eleven ABCB1, VDR and TPMT VIP variants were found between Jordanian Chechens and other populations. In our study, most populations that are similar to Chechens are those from South Asian, European (Finnish) and European, including: Utah residents with Northern and Western European ancestry, Toscani in Italia, Mexican ancestry in Los Angeles and Circassian from Jordan. The level of similarity between Chechens and those populations means that they might have shared high levels of gene flow in the past. The results obtained in this study will contribute to the worldwide pharmacogenomic databases and provide valuable information for future studies and better individualized treatments.

Background: The present article is related to in-vitro and in-vivo herb-drug interaction studies. Objectives: This study aimed to investigate the effect of Nigella sativa and fenugreek on the pharmacodynamics and pharmacokinetics of amlodipine. Method: Hypertensive rats of group-I were treated with amlodipine and rats of group-II and III were treated with N. sativa, and N. sativa + amlodipine and fenugreek, and fenugreek + amlodipine, respectively. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean blood pressure (MBP) of group-I, II and III rats were measured by the “tail-cuff system”. Results: N. sativa, as well as fenugreek, reduced the SBP, DBP and MBP. Simultaneously, administration of fenugreek + amlodipine or N. sativa + amlodipine showed better control of BP. Individually, fenugreek, as well as N. sativa, showed a surprising reduction in the heart rate. There was no remarkable effect of any of these two herbs on Cmax, AUC0-t, Kel, and terminal elimination half-life of amlodipine, but fenugreek altered the Tmax of amlodipine significantly, from 2 ± 1.2h in control to 7.2 ± 1.7h in fenugreek treated group, probably by delaying the absorption. Conclusion: Results of pharmacodynamics and pharmacokinetics studies suggested that simultaneous administration of fenugreek or N. sativa with amlodipine improved the pharmacological response of amlodipine in hypertensive rats, though there was no remarkable change in pharmacokinetic parameters (Cmax, Kel, elimination t1/2, and AUC0-t).