- Systematic review of mutations associated with resistance to the new and repurposed Mycobacterium tuberculosis drugs bedaquiline, clofazimine, linezolid, delamanid and pretomanid. [Journal Article]J Antimicrob Chemother. 2020 May 03 [Online ahead of print]JA
- CONCLUSIONS: This systematic review supports the use of molecular methods for linezolid resistance detection. Resistance mechanisms involving non-essential genes show a diversity of mutations that will challenge molecular diagnosis of bedaquiline and nitroimidazole resistance. Combined phenotypic and genotypic surveillance is needed for these drugs in the short term.
- Reduced susceptibility and resistance to bedaquiline in clinical M. tuberculosis isolates. [Journal Article]J Infect. 2020 May; 80(5):527-535.JI
- CONCLUSIONS: Bedaquiline treatment leads to an elevated bedaquiline MIC and the acquisition of mmpR and atpE gene mutations in tuberculosis strains. The standardisation of bedaquiline phenotypic susceptibility testing is urgently needed based on observed discrepancies between our study and previous studies and differences in solid and liquid media MIC determinations.
- Highly sensitive and rapid determination of azathioprine metabolites in whole blood lysate by liquid chromatography-tandem mass spectrometry. [Journal Article]J Chromatogr B Analyt Technol Biomed Life Sci. 2020 Jan 01; 1136:121802.JC
- Individualized therapy involves genetic test of drug metabolism, which provides information about the initial dose and therapeutic drug monitoring for adjusting the subsequent dose. Consequently, toxic side effects are expected to be minimized and therapeutic effects to be maximized. In this study, an ultra-performance liquid chromatography tandem mass spectrometry method that was specific, accur…
Individualized therapy involves genetic test of drug metabolism, which provides information about the initial dose and therapeutic drug monitoring for adjusting the subsequent dose. Consequently, toxic side effects are expected to be minimized and therapeutic effects to be maximized. In this study, an ultra-performance liquid chromatography tandem mass spectrometry method that was specific, accurate and sensitive was developed to simultaneously determine azathioprine two metabolites, 6-thioguanine nucleotides (6-TGN) and 6-methyl-mercaptopurine riboside (6-MMPr) in the whole blood lysate. We precipitated the sample by trifluoroacetic acid under the protection of dithiothreitol, with 6-MMPr and 6-TGN being hydrolyzed to produce 6-methymercaptopurine and 6-thioguanine. In the chromatographic separation, Waters ACQUITY BEH C18 (2.1 × 100 mm, 1.7 μm) chromatographic column was applied and gradient elution was conducted with 0.02 mol/L ammonium acetate buffer (which contains 0.3% formic acid) and acetonitrile at a flow rate of 0.4 ml/min. Tandem mass spectrometry in multiple reaction monitoring mode was applied for detection via electrospray ionization source in positive ionization mode. The analyzing process lasted for no more than 2 min. The calibration curve for each metabolite fitted a least squares model (weighed 1/X) from 1.25 to 5000 ng/ml (r2 > 0.99). The ion pairs were detected as 6-MMP m/z 167.07 → 152.15, 6-TG m/z 168.06 → 134.13, and internal standard m/z 171.07 → 137.14. Under the guidance of FDA guidelines for bioanalytical method validation, we carried out validation and obtained satisfactory results. The method was successfully utilized for monitoring the concentrations of each metabolite from 65 affected patients who had received azathioprine maintenance therapy and achieved optimal results.
- Different Suture Materials for Arthroscopic Transtibial Pull-out Repair of Medial Meniscal Posterior Root Tears: A Human Biomechanical Study. [Journal Article]Orthop J Sports Med. 2019 Sep; 7(9):2325967119873274.OJ
- CONCLUSIONS: The meniscal root repair construct with UHMWPE suture tape may be stronger and less prone to displacement than that with standard suture or UHMWPE suture.
- Collagenous Ultrastructure of the Torn Medial Meniscus Posterior Root: A Transmission Electron Microscopy Study. [Journal Article]Am J Sports Med. 2019 11; 47(13):3221-3228.AJ
- CONCLUSIONS: This study showed that torn MMPRs had decreased numbers and disorganized courses of collagen fibers. The structural problem of torn MMPRs can negatively affect meniscal healing, function, and long-term survival after root repair.
- Implementation of a multi-modal pain regimen to decrease inpatient opioid exposure after injury. [Journal Article]Am J Surg. 2019 12; 218(6):1122-1127.AJ
- CONCLUSIONS: The introduction of a multi-modal pain regimen resulted in significant reduction in in-patient opioid exposure after injury. The reduction in inpatient opioid use from 2010 to 2017 was equivalent to 11 mg less oxycodone or 17 mg less hydrocodone per patient per day. Additionally, use of the MMPR was associated with a reduction in NRS pain scores.
- Oral antidiabetic medication adherence and glycaemic control among patients with type 2 diabetes mellitus: a cross-sectional retrospective study in a tertiary hospital in Saudi Arabia. [Journal Article]BMJ Open. 2019 07 23; 9(7):e029280.BO
- CONCLUSIONS: The study findings support the growing concern of non-adherence to OADs among patients with T2DM in Saudi Arabia. Decision makers have to invest in behavioural interventions that will boost medication adherence rates. This is particularly important in patients with polypharmacy and high burden of comorbid conditions.
- Examination of bedaquiline- and linezolid-resistant Mycobacterium tuberculosis isolates from the Moscow region. [Journal Article]J Antimicrob Chemother. 2017 07 01; 72(7):1901-1906.JA
- CONCLUSIONS: The introduction of novel drugs into treatment must be accompanied by continuous phenotypic susceptibility testing and the analysis of genetic determinants of resistance.
- Medical cannabis access, use, and substitution for prescription opioids and other substances: A survey of authorized medical cannabis patients. [Journal Article]Int J Drug Policy. 2017 04; 42:30-35.IJ
- CONCLUSIONS: The finding that patients report its use as a substitute for prescription drugs supports prior research on medical cannabis users; however, this study is the first to specify the classes of prescription drugs for which cannabis it is used as a substitute, and to match this substitution to specific diagnostic categories. The findings that some authorized patients purchase cannabis from unregulated sources and that a significant percentage of patients were charged for medical cannabis recommendations highlight ongoing policy challenges for this federal program.
- The impact of adjunctive guanfacine extended release on stimulant adherence in children/adolescents with attention-deficit/hyperactivity disorder. [Journal Article]J Comp Eff Res. 2017 Mar; 6(2):109-125.JC
- CONCLUSIONS: Among patients nonadherent to stimulants, GXR augmentation was associated with increased stimulant adherence.
- The glutathione transferase Mu null genotype leads to lower 6-MMPR levels in patients treated with azathioprine but not with mercaptopurine. [Journal Article]Pharmacogenomics J. 2018 01; 18(1):160-166.PJ
- The conversion of azathioprine (AZA) to mercaptopurine (MP) is mediated by glutathione transferase Mu1 (GSTM1), alpha1 (GSTA1) and alpha2 (GSTA2). We designed a case-control study with data from the TOPIC trial to explore the effects of genetic variation on steady state 6-methylmercaptopurine ribonucleotide (6-MMPR) and 6-thioguanine nucleotide (6-TGN) metabolite levels. We included 199 patients …
The conversion of azathioprine (AZA) to mercaptopurine (MP) is mediated by glutathione transferase Mu1 (GSTM1), alpha1 (GSTA1) and alpha2 (GSTA2). We designed a case-control study with data from the TOPIC trial to explore the effects of genetic variation on steady state 6-methylmercaptopurine ribonucleotide (6-MMPR) and 6-thioguanine nucleotide (6-TGN) metabolite levels. We included 199 patients with inflammatory bowel disease (126 on AZA and 73 on MP). GSTM1-null genotype carriers on AZA had two-fold lower 6-MMPR levels than AZA users carrying one or two copies of GSTM1 (2239 (1006-4587) versus 4371 (1897-7369) pmol/8 × 108 RBCs; P<0.01). In patients on MP (control group) 6-MMPR levels were comparable (6195 (1551-10712) versus 6544 (1717-11600) pmol/8 × 108 RBCs; P=0.84). The 6-TGN levels were not affected by the GSTM1 genotype. The presence of genetic variants in GSTA1 and GSTA2 was not related to the 6-MMPR and 6-TGN levels.
- Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease. [Randomized Controlled Trial]Aliment Pharmacol Ther. 2017 02; 45(3):391-402.AP
- CONCLUSIONS: In more than 80% of patients, thiopurine-induced hepatotoxicity could be explained by elevated T1 6-MMPR concentrations and the independent risk factors age, gender and BMI, allowing personalised thiopurine treatment in IBD to prevent early failure.
- NUDT15 polymorphisms are better than thiopurine S-methyltransferase as predictor of risk for thiopurine-induced leukopenia in Chinese patients with Crohn's disease. [Journal Article]Aliment Pharmacol Ther. 2016 11; 44(9):967-975.AP
- CONCLUSIONS: In Chinese patients, it is strongly recommended to detect NUDT15 genotype rather than TPMT before initiating thiopurine drugs. 6TGN concentration should be routinely monitored in CD patients with NUDT15 wild type. As for CT genotype, starting at low dose and careful monitoring for leukopenia and 6TGN levels is recommended.
- Early Assessment of Thiopurine Metabolites Identifies Patients at Risk of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease. [Randomized Controlled Trial]J Crohns Colitis. 2017 Feb; 11(2):175-184.JC
- CONCLUSIONS: In ~80% of patients, leukopenia could be explained by T1 6-TGN and/or 6-MMPR elevations. Validation of the predictive model is needed before implementing in clinical practice.
- Routinely Established Skewed Thiopurine Metabolism Leads to a Strikingly High Rate of Early Therapeutic Failure in Patients With Inflammatory Bowel Disease. [Journal Article]Ther Drug Monit. 2015 Dec; 37(6):797-804.TD
- CONCLUSIONS: This study demonstrates that a routinely established skewed metabolism is a major risk factor for future thiopurine failure in patients with IBD. These observations imply that routine thiopurine metabolite measurements may be used as a prognostic tool to identify those patients with an aberrant-skewed metabolism at an early stage, possibly benefitting from therapy adjustments.
- Impact of adherence and weight loss on glycemic control in patients with type 2 diabetes: cohort analyses of integrated medical record, pharmacy claims, and patient-reported data. [Journal Article]J Manag Care Spec Pharm. 2014 Jul; 20(7):691-700.JM
- CONCLUSIONS: This study has provided additional evidence in a managed, integrated setting that in patients treated for T2DM, weight loss is associated with good glycemic control. Adherence is associated with weight loss according to self-report, but not claims-based adherence measures. Adherence is also associated with glycemic control as measured by the 2 different methods. This study adds to the body of literature highlighting the importance of adherence as well as weight loss in achieving good glycemic control. The fact that the association of weight loss and adherence on glycemic control outcomes was significant regardless of medication adherence method is important in payer-provider collaborations, where access to data sources to evaluate adherence may vary. This study also supports continued investment in weight loss and adherence programs in the management of patients with T2DM.
- The pharmacokinetic effect of adalimumab on thiopurine metabolism in Crohn's disease patients. [Journal Article]J Crohns Colitis. 2014 Feb; 8(2):120-8.JC
- CONCLUSIONS: In this study in Crohn's disease patients no pharmacokinetic interaction was shown between adalimumab and the conventional thiopurines, azathioprine and mercaptopurine.
- Mucosal improvement in patients with moderate to severe postoperative endoscopic recurrence of Crohn's disease and azathioprine metabolite levels. [Multicenter Study]Inflamm Bowel Dis. 2013 Mar; 19(3):590-8.IB
- CONCLUSIONS: Our post hoc analysis from a double-blind, randomized trial suggests that higher RBC 6-TGN levels are associated with endoscopic improvement in patients with severe postoperative endoscopic recurrence of CD. Thus, our study provides first evidence on the utility of monitoring of thiopurine metabolites to achieve mucosal response in CD.
- Improved antiretroviral refill adherence in HIV-focused community pharmacies. [Journal Article]J Am Pharm Assoc (2003). 2012 Sep-Oct; 52(5):e67-73.JA
- CONCLUSIONS: For HIV-positive patients struggling with antiretroviral adherence, clinicians may consider minimizing pill burden with combination tablets and referral to an HIV-focused pharmacy.
- Effects of antiepileptic drug characteristics on medication adherence. [Journal Article]Epilepsy Behav. 2012 Apr; 23(4):437-41.EB
- CONCLUSIONS: Our findings contradict some commonly held beliefs on medication adherence and suggest that specific AED characteristics may be superseded by factors such as overall patient satisfaction with the drug regimen.
- Influence of 5-aminosalicylic acid on 6-thioguanosine phosphate metabolite levels: a prospective study in patients under steady thiopurine therapy. [Clinical Trial]Br J Pharmacol. 2010 Jul; 160(5):1083-91.BJ
- CONCLUSIONS: Individual 6-TGN metabolites increased after addition of 5-ASA, but 6-MMPR-levels and the 6-MMPR/6-TGN ratios decreased. Further studies are needed to decide whether this pharmacokinetic interaction would result in improvement of efficacy and/or increased risk of toxicity of AZA.
- The role of xanthine oxidase in thiopurine metabolism: a case report. [Case Reports]Ther Drug Monit. 2007 Dec; 29(6):845-8.TD
- Azathioprine (AZA) is widely used in the treatment of autoimmune inflammatory diseases. AZA is normally rapidly and almost completely converted to 6-mercaptopurine (6-MP) in the liver, which is further metabolized into a variety of pharmacologic active thiopurine metabolites. 6-MP is catabolized by xanthine oxidase (XO) to the inactive metabolite 6-thiouric acid. The authors report the case of a …
Azathioprine (AZA) is widely used in the treatment of autoimmune inflammatory diseases. AZA is normally rapidly and almost completely converted to 6-mercaptopurine (6-MP) in the liver, which is further metabolized into a variety of pharmacologic active thiopurine metabolites. 6-MP is catabolized by xanthine oxidase (XO) to the inactive metabolite 6-thiouric acid. The authors report the case of a woman with chronic autoimmune pancreatitis unable to form active thiopurine metabolites. The 55-year-old woman presented with weight loss, progressive elevation of liver transaminases, and serum amylase. She was treated with prednisolone 30 mg/day (1 mg/kg) and AZA was increased to 75 mg/day (2.5 mg/kg); this was later increased to 150 mg/day (5 mg/kg). Despite good patient compliance, the active metabolites of AZA, 6-thioguanine nucleotides (6-TGN), and 6-methylmercaptopurine ribonucleotides (6-MMPR) could not be detected in the erythrocytes (RBC). Subsequently, AZA was switched to high-dose 6-MP (2.5 mg/kg) and the XO inhibitor allopurinol was added. After 1 week, this combination led to a high 6-TGN level of 616 pmol/8 x 10(8) RBC and a 6-MMPR level of 1319 pmol/8 x 10(8) RBC. Three weeks after starting treatment, 6-TGN and 6-MMPR even reached toxic levels (1163 pmol/8 x 10(8) RBC and 10015 pmol/8 x 10(8) RBC, respectively) so that 6-MP treatment was discontinued. To elucidate this finding, 6-MP (1.7 mg/kg) was prescribed for 3 days without allopurinol. The woman was not able to form active thiopurine metabolites. According to the authors, this is the first report of a patient unable to form detectable active thiopurine metabolites on AZA and 6-MP therapy despite good patient compliance. High XO activity led to an inability to form detectable levels of active thiopurine metabolites 6-TGN and 6-MMPR. This finding emphasizes the important role of XO in the biotransformation of thiopurines.
- Hepatotoxicity of 6-mercaptopurine (6-MP) and Azathioprine (AZA) in adult IBD patients. [Journal Article]Am J Gastroenterol. 2007 Nov; 102(11):2488-94.AJ
- CONCLUSIONS: 6-MP/AZA-induced hepatotoxicity is uncommon in the adult population. Although hepatotoxicity is associated with higher mean 6-MMPR levels, the sensitivity and specificity of 6-MMPR for drug-induced hepatotoxicity was poor. Monitoring liver tests in patients on 6-MP/AZA is suggested, and dose reduction or cessation of 6-MP/AZA, even with high 6-MMPR levels, should be reserved for patients with elevated aminotransferases.
- Monitoring of thiopurine methyltransferase activity in postsurgical patients with Crohn's disease during 1 year of treatment with azathioprine or mesalazine. [Randomized Controlled Trial]Ther Drug Monit. 2007 Feb; 29(1):1-5.TD
- Thiopurine methyltransferase (TPMT) activity determines biotransformation of azathioprine and, thereby, drug efficacy and safety. Evaluation of a possible long-term effect of mesalazine or azathioprine on TPMT activity is of particular clinical importance because both drugs can to be given for several years in inflammatory bowel disease. Monitoring of TPMT activity and three thiopurine metabolite…
Thiopurine methyltransferase (TPMT) activity determines biotransformation of azathioprine and, thereby, drug efficacy and safety. Evaluation of a possible long-term effect of mesalazine or azathioprine on TPMT activity is of particular clinical importance because both drugs can to be given for several years in inflammatory bowel disease. Monitoring of TPMT activity and three thiopurine metabolites was performed prospectively during a 1 year postoperative period in 21 patients with Crohn's disease randomly assigned to azathioprine (2.0-2.5 mg/kg per day) or mesalazine (4 g/day). TPMT activity did not change significantly within each treatment group during 52 weeks. At any study visit, TPMT activity was not different between 13 patients on azathioprine and eight patients on mesalazine. Concentrations of 6-thioguanine nucleotides (6-TGN, active moiety of azathioprine) and 6-methyl-mercaptopurine ribonucleotides (6-MMPR) did not alter significantly during the observation period, except for a slight decrease in 6-TGN levels when comparing the first with the last visit. In this first report of serial monitoring of 6-methyl-thioguanine nucleotides (6-MTGN) in patients with inflammatory bowel disease taking azathioprine, high levels of 6-TGN were correlated with high levels of 6-MTGN, with the mean 6-TGN:6-MTGN ratio being 2.4. In a well-standardized clinical setting of inflammatory bowel disease, neither mesalazine nor azathioprine significantly affected TPMT activity during a whole year of treatment.
- Substrate analogs induce an intermediate conformational change in Toxoplasma gondii adenosine kinase. [Journal Article]Acta Crystallogr D Biol Crystallogr. 2007 Feb; 63(Pt 2):126-34.AC
- Adenosine kinase (AK) is a key enzyme in purine metabolism in the ubiquitous intracellular parasite Toxoplasma gondii and is a potential chemotherapeutic target for the treatment of T. gondii infections. To better understand the structure-activity relationship of 6-substituted purine ribosides, the structures of the T. gondii AK-N6,N6-dimethyladenosine (DMA) complex, the AK-DMA-AMP-PCP complex, t…
Adenosine kinase (AK) is a key enzyme in purine metabolism in the ubiquitous intracellular parasite Toxoplasma gondii and is a potential chemotherapeutic target for the treatment of T. gondii infections. To better understand the structure-activity relationship of 6-substituted purine ribosides, the structures of the T. gondii AK-N6,N6-dimethyladenosine (DMA) complex, the AK-DMA-AMP-PCP complex, the AK-6-methyl mercaptopurine riboside (MMPR) complex and the AK-MMPR-AMP-PCP complex were determined to 1.35, 1.35, 1.75 and 1.75 A resolution, respectively. These structures reveal a conformation intermediate between open and closed, with a small lid-domain rotation of 12 degrees . Residues Gly143-X-X-Gly146 undergo torsional changes upon substrate binding, which together with a Gly68-Gly69 switch induces a hinge bending of the lid domain. The intermediate conformation suggests that ATP binding is independent of adenosine binding. Orienting the gamma-phosphate group of ATP into the optimal catalytic position may be the last step before the onset of chemical catalysis and may require the translocation of Arg136 following the complete closure of the lid domain. 6-Substituted purine-nucleoside analogs are accommodated in a hydrophobic cavity. Modification at the N6 or C6 position of the nucleoside would affect the interactions with the surrounding residues and the binding affinity.
- Induction of meiotic maturation in mouse oocytes by adenosine analogs. [Journal Article]Mol Reprod Dev. 2006 Sep; 73(9):1159-68.MR
- In this study we have examined the meiosis-inducing influence of adenosine analogs in mouse oocytes. When a varied group of nucleosides and nucleotides were tested on overnight cultures of hypoxanthine-arrested, cumulus cell-enclosed oocytes (CEO), halogenated adenosine nucleosides, but not native adenosine, exhibited a significant meiosis-inducing capability. When tested under a variety of condi…
In this study we have examined the meiosis-inducing influence of adenosine analogs in mouse oocytes. When a varied group of nucleosides and nucleotides were tested on overnight cultures of hypoxanthine-arrested, cumulus cell-enclosed oocytes (CEO), halogenated adenosine nucleosides, but not native adenosine, exhibited a significant meiosis-inducing capability. When tested under a variety of conditions, meiotic induction by 8-bromo-adenosine (8-Br-Ado) and a second adenosine analog, methylmercaptopurine riboside (MMPR), was especially potent in denuded oocytes (DO) compared to CEO and was not dependent on the type of inhibitor chosen to maintain meiotic arrest. Germinal vesicle breakdown (GVB) was stimulated with rapid kinetics and was preceded by an increase in AMP-activated protein kinase (AMPK) activity. Moreover, compound C, an inhibitor of AMPK, blocked the meiosis-inducing activities of both adenosine analogs. When tested for an effect on meiotic progression to metaphase II (MII) in spontaneously maturing CEO, 8-Br-Ado and the AMPK activator, 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR), increased the percentage of MII-stage oocytes, but MMPR decreased this number. Adenosine and inhibitors of de novo purine synthesis had no effect on the completion of maturation, while compound C suppressed this process. These results support the proposition that oocyte AMPK mediates the positive influence of AICAR and 8-Br-Ado on both the initiation and completion of meiotic maturation. The role of AMPK in MMPR action is less clear.
- Status of methylthioadenosine phosphorylase and its impact on cellular response to L-alanosine and methylmercaptopurine riboside in human soft tissue sarcoma cells. [Journal Article]Oncol Res. 2004; 14(7-8):373-9.OR
- The aim of this study was to examine the expression of methylthioadenosine phosphorylase (MTAP) in 21 fresh tumor samples from patients with soft tissue sarcomas (STS) and 11 human soft tissue sarcoma cell lines, and to determine if loss of expression of this enzyme was correlated with increased sensitivity to L-alanosine and/or 6-methylmercaptopurine. We used a polyclonal antibody to measure the…
The aim of this study was to examine the expression of methylthioadenosine phosphorylase (MTAP) in 21 fresh tumor samples from patients with soft tissue sarcomas (STS) and 11 human soft tissue sarcoma cell lines, and to determine if loss of expression of this enzyme was correlated with increased sensitivity to L-alanosine and/or 6-methylmercaptopurine. We used a polyclonal antibody to measure the expression of MTAP in soft tissue sarcoma cell lines and in fresh tumor samples. Transfection of the HT-1080 cell line with a plasmid containing the cDNA for the MTAP gene was also performed to generate cell lines for in vitro and in vivo comparative sensitivity studies. MTAP was not expressed in 8 of 21 fresh STS tumors. The expression of MTAP was also not detectable in 3 of the 11 soft tissue sarcoma cell lines (HT-1080, HS42, and M-9 110). These three cell lines were more sensitive to L-alanosine, a potent inhibitor of de novo AMP synthesis, and to an inhibitor of de novo purine nucleotide synthesis, 6-methylmercaptopurine riboside (MMPR). The IC50 values for L-alanosine and MMPR were >20-fold lower in MTAP-deficient cells than in MTAP-positive cells. Restoration of MTAP into HT-1080 MTAP-deficient cells also led to decreased sensitivity to L-alanosine and MMPR. An in vivo study using HT-1080 cell tumors with and without MTAP expression confirmed that tumors lacking MTAP were more sensitive to L-alanosine than tumors expressing MTAP. These results provide the basis for selective therapy using inhibitors of de novo purine nucleotide synthesis such as L-alanosine or MMPR to treat patients with STS lacking this enzyme.
- Pharmacokinetics of 6-mercaptopurine in patients with inflammatory bowel disease: implications for therapy. [Clinical Trial]Ther Drug Monit. 2004 Jun; 26(3):311-8.TD
- Proper prospective pharmacokinetic studies of 6-mercaptopurine (6-MP) in inflammatory bowel disease (IBD) patients are lacking. As a result, conflicting recommendations have been made for metabolite monitoring in routine practice. The authors have evaluated 6-MP pharmacokinetics in IBD patients, including the genetic background for thiopurine methyltransferase (TPMT). Red blood cell (RBC) 6-thiog…
Proper prospective pharmacokinetic studies of 6-mercaptopurine (6-MP) in inflammatory bowel disease (IBD) patients are lacking. As a result, conflicting recommendations have been made for metabolite monitoring in routine practice. The authors have evaluated 6-MP pharmacokinetics in IBD patients, including the genetic background for thiopurine methyltransferase (TPMT). Red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine ribonucleotide (6-MMPR) concentrations were measured in 30 IBD patients at 1, 2, 4, and 8 weeks after starting 6-MP, 50 mg once daily. Outcome measures included mean 6-TGN and 6-MMPR concentrations (+/- 95% confidence interval, CI95%) and their associations with TPMT genotype, 6-MP dose, and hematologic, hepatic, pancreatic, and efficacy parameters during the 8-week period. Steady-state concentrations were reached after 4 weeks, indicating a half-life of approximately 5 days for both 6-TGN and 6-MMPR; the concentrations were 368 (CI95% 284-452) and 2837 (CI95% 2101-3573) pmol/8 x 10 RBCs, respectively. Large interpatient variability occurred at all time points. TPMT genotype correlated with 6-TGN concentrations (0.576, P < 0.01), and patients with mutant alleles had a relative risk (RR) of 12.0 (CI95% 1.7-92.3) of developing leukopenia. A 6-MMPR/6-TGN ratio less than 11 was associated with therapeutic efficacy. Based on this pharmacokinetic analysis, therapeutic drug monitoring is essential for rational 6-MP dosing.
- 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. [Clinical Trial]Gastroenterology. 2002 Apr; 122(4):904-15.G
- CONCLUSIONS: Serial metabolite monitoring identifies a novel phenotype of IBD patients resistant to 6-MP/AZA therapy biochemically characterized by suboptimal 6-TGN and preferential 6-MMPR production upon dose escalation.
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- An open-label pilot study using thioguanine as a therapeutic alternative in Crohn's disease patients resistant to 6-mercaptopurine therapy. [Clinical Trial]Inflamm Bowel Dis. 2001 Aug; 7(3):181-9.IB
- CONCLUSIONS: 6-TG was a safer and more efficacious thiopurine in this subgroup of IBD patients resistant to 6-MP therapy. Larger controlled trials are warranted to further evaluate both the short- and long-term safety and efficacy in this subgroup of patients as well as a broader spectrum of IBD patients.