Paul Watkins

Summary

Affiliation: University of North Carolina
Country: USA

Publications

  1. ncbi request reprint Common allelic variants of cytochrome P4503A4 and their prevalence in different populations
    Jatinder K Lamba
    Department of Pharmaceutical Sciences, St Jude Children s Research Hospital, Memphis, Tennessee 38105, USA
    Pharmacogenetics 12:121-32. 2002
  2. ncbi request reprint Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial
    Paul B Watkins
    Department of Medicine, University of North Carolina, Chapel Hill, USA
    JAMA 296:87-93. 2006
  3. doi request reprint Drug safety sciences and the bottleneck in drug development
    P B Watkins
    Hamner University of North Carolina, Institute for Drug Safety Sciences, Schools of Medicine and Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
    Clin Pharmacol Ther 89:788-90. 2011
  4. doi request reprint Biomarkers for the diagnosis and management of drug-induced liver injury
    Paul B Watkins
    University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
    Semin Liver Dis 29:393-9. 2009
  5. ncbi request reprint Idiosyncratic liver injury: challenges and approaches
    Paul B Watkins
    University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
    Toxicol Pathol 33:1-5. 2005
  6. ncbi request reprint Clinical pattern of zileuton-associated liver injury: results of a 12-month study in patients with chronic asthma
    Paul B Watkins
    University of North Carolina Hospital, Chapel Hill, North Carolina 27599 7600, USA
    Drug Saf 30:805-15. 2007
  7. ncbi request reprint Drug-induced liver injury: summary of a single topic clinical research conference
    Paul B Watkins
    University of North Carolina, Chapel Hill, NC, USA
    Hepatology 43:618-31. 2006
  8. doi request reprint Evaluation of drug-induced serious hepatotoxicity (eDISH): application of this data organization approach to phase III clinical trials of rivaroxaban after total hip or knee replacement surgery
    Paul B Watkins
    Hamner UNC Institute for Drug Safety Sciences, 6 Davis Drive, Research Triangle Park, NC 27709, USA
    Drug Saf 34:243-52. 2011
  9. ncbi request reprint Hepatic but not intestinal CYP3A4 displays dose-dependent induction by efavirenz in humans
    Stephane Mouly
    General Clinical Research Center, University of North Carolina, Chapel Hill 27599, USA
    Clin Pharmacol Ther 72:1-9. 2002
  10. ncbi request reprint Variation in oral clearance of saquinavir is predicted by CYP3A5*1 genotype but not by enterocyte content of cytochrome P450 3A5
    Stéphane J Mouly
    General Clinical Research Center, School of Pharmacy, and Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, USA
    Clin Pharmacol Ther 78:605-18. 2005

Research Grants

  1. Hepatoxicity Clincal Research Network
    Paul Watkins; Fiscal Year: 2007
  2. FURANOCOUMARINS AND DRUGS EFFECT ON CYP3A4
    Paul Watkins; Fiscal Year: 2007
  3. GENERAL CLINICAL RESEARCH CENTERS ANNUAL MEETING
    Paul Watkins; Fiscal Year: 2006

Collaborators

Detail Information

Publications46

  1. ncbi request reprint Common allelic variants of cytochrome P4503A4 and their prevalence in different populations
    Jatinder K Lamba
    Department of Pharmaceutical Sciences, St Jude Children s Research Hospital, Memphis, Tennessee 38105, USA
    Pharmacogenetics 12:121-32. 2002
    ..None of the 28 CYP3A4 SNPs identified in CYP3A4 phenotyped persons (most individuals being heterozygous for any CYP3A4 variant) was associated with low hepatic CYP3A4 protein expression or low CYP3A4 activity in vivo...
  2. ncbi request reprint Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial
    Paul B Watkins
    Department of Medicine, University of North Carolina, Chapel Hill, USA
    JAMA 296:87-93. 2006
    ..During a clinical trial of a novel hydrocodone/acetaminophen combination, a high incidence of serum alanine aminotransferase (ALT) elevations was observed...
  3. doi request reprint Drug safety sciences and the bottleneck in drug development
    P B Watkins
    Hamner University of North Carolina, Institute for Drug Safety Sciences, Schools of Medicine and Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
    Clin Pharmacol Ther 89:788-90. 2011
    ..If the drug is ultimately approved, this detour will result in costs and potential revenue loss to the sponsor of well over $1 billion...
  4. doi request reprint Biomarkers for the diagnosis and management of drug-induced liver injury
    Paul B Watkins
    University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
    Semin Liver Dis 29:393-9. 2009
    ..Such discovery efforts will require the establishment of well-annotated serum and urine banks from prospective clinical trials of drugs capable of causing progressive liver injury...
  5. ncbi request reprint Idiosyncratic liver injury: challenges and approaches
    Paul B Watkins
    University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
    Toxicol Pathol 33:1-5. 2005
    ..This network should provide heretofore missing resources required to address the problem...
  6. ncbi request reprint Clinical pattern of zileuton-associated liver injury: results of a 12-month study in patients with chronic asthma
    Paul B Watkins
    University of North Carolina Hospital, Chapel Hill, North Carolina 27599 7600, USA
    Drug Saf 30:805-15. 2007
    ..To more fully characterise the hepatic effects of zileuton, and to establish appropriate monitoring guidelines, a 12-month open-label, safety surveillance study was conducted prior to FDA approval...
  7. ncbi request reprint Drug-induced liver injury: summary of a single topic clinical research conference
    Paul B Watkins
    University of North Carolina, Chapel Hill, NC, USA
    Hepatology 43:618-31. 2006
    ..The presentations spanned many different areas of DILI, and included novel data concerning mechanisms of hepatotoxicity, new "omics" approaches, and the challenges of improving causation assessment...
  8. doi request reprint Evaluation of drug-induced serious hepatotoxicity (eDISH): application of this data organization approach to phase III clinical trials of rivaroxaban after total hip or knee replacement surgery
    Paul B Watkins
    Hamner UNC Institute for Drug Safety Sciences, 6 Davis Drive, Research Triangle Park, NC 27709, USA
    Drug Saf 34:243-52. 2011
    ....
  9. ncbi request reprint Hepatic but not intestinal CYP3A4 displays dose-dependent induction by efavirenz in humans
    Stephane Mouly
    General Clinical Research Center, University of North Carolina, Chapel Hill 27599, USA
    Clin Pharmacol Ther 72:1-9. 2002
    ....
  10. ncbi request reprint Variation in oral clearance of saquinavir is predicted by CYP3A5*1 genotype but not by enterocyte content of cytochrome P450 3A5
    Stéphane J Mouly
    General Clinical Research Center, School of Pharmacy, and Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, USA
    Clin Pharmacol Ther 78:605-18. 2005
    ..The polymorphic CYP3A5 has also been shown to influence the saquinavir metabolite/parent urinary ratio, suggesting a role for CYP3A5...
  11. ncbi request reprint A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction
    Mary F Paine
    Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina, Chapel Hill, NC, USA
    Am J Clin Nutr 83:1097-105. 2006
    ..Furanocoumarins have been identified as major CYP3A4 inhibitors contained in the juice, but their contribution to the GFJ effect in vivo remains unclear...
  12. ncbi request reprint Identification of a novel route of extraction of sirolimus in human small intestine: roles of metabolism and secretion
    Mary F Paine
    General Clinical Research Center and Division of Pharmacotherapy, University of North Carolina, Chapel Hill, North Carolina 27599, USA
    J Pharmacol Exp Ther 301:174-86. 2002
    ....
  13. doi request reprint Quantitative analyses and transcriptomic profiling of circulating messenger RNAs as biomarkers of rat liver injury
    Barbara A Wetmore
    The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709 2137, USA
    Hepatology 51:2127-39. 2010
    ..Finally, gene expression microarray analysis of the plasma following DGAL and APAP treatment revealed chemical-specific profiles...
  14. ncbi request reprint Do men and women differ in proximal small intestinal CYP3A or P-glycoprotein expression?
    Mary F Paine
    General Clinical Research Center, Room 3005, Bldg APCF, CB 7600, UNC Hospitals, Chapel Hill, NC 27599 7600, USA
    Drug Metab Dispos 33:426-33. 2005
    ..Ramifications of lower intestinal CYP3A4 content in post- versus premenopausal women require further investigation...
  15. ncbi request reprint Two major grapefruit juice components differ in time to onset of intestinal CYP3A4 inhibition
    Mary F Paine
    General Clinical Research Center, Room 3005 Bldg APCF, CB 7600, UNC Hospitals, Chapel Hill, NC 27599 7600, USA
    J Pharmacol Exp Ther 312:1151-60. 2005
    ..However, foods containing BG but not DHB (e.g., lime juice) could produce a substrate-dependent interaction with drugs consumed concomitantly, but a substrate-independent interaction with drugs taken several hours after food consumption...
  16. ncbi request reprint New insights into drug absorption: studies with sirolimus
    Mary F Paine
    General Clinical Research Center and Division of Pharmacotherapy, University of North Carolina, Chapel Hill, North Carolina 27599 7600, USA
    Ther Drug Monit 26:463-7. 2004
    ..This new insight into the intestinal elimination of sirolimus, which was not identified using traditional drug metabolism/transport screening methods, may represent another source for the limited absorption of sirolimus...
  17. ncbi request reprint Two major grapefruit juice components differ in intestinal CYP3A4 inhibition kinetic and binding properties
    Mary F Paine
    General Clinical Research Center, Room 3005 Bldg APCF, CB 7600, UNC Hospitals, Chapel Hill, NC 27599 7600, USA
    Drug Metab Dispos 32:1146-53. 2004
    ..Results also emphasize the importance of appropriate substrate selection when designing inhibition studies involving dietary constituents...
  18. ncbi request reprint Further characterization of a furanocoumarin-free grapefruit juice on drug disposition: studies with cyclosporine
    Mary F Paine
    School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599 7360, USA
    Am J Clin Nutr 87:863-71. 2008
    ..It remains unclear whether furanocoumarins mediate drug-GFJ interactions involving CYP3A4 substrates that are also P-glycoprotein substrates...
  19. ncbi request reprint CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults
    Raymond C Givens
    General Clinical Research Center, University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA
    J Appl Physiol 95:1297-300. 2003
    ..3 mmHg. We speculate whether a high CYP3A5 expressor allele frequency among African-Americans may contribute to a high prevalence of sodium-sensitive hypertension in this population...
  20. pmc Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States
    Naga Chalasani
    Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    Gastroenterology 135:1924-34, 1934.e1-4. 2008
    ..This report summarizes the causes, clinical features, and outcomes from the first 300 patients enrolled...
  21. ncbi request reprint Contributions of CYP3A4, P-glycoprotein, and serum protein binding to the intestinal first-pass extraction of saquinavir
    Stéphane J Mouly
    General Clinical Research Center, University of North Carolina Hospitals, Chapel Hill, NC 27599 7600, USA
    J Pharmacol Exp Ther 308:941-8. 2004
    ..We conclude that variable intestinal first-pass extraction of saquinavir in human immunodeficiency virus-infected patients could reflect variation in P-gp-mediated efflux and/or CYP3A4-catalyzed metabolism, but not in blood AAG levels...
  22. doi request reprint Using controlled clinical trials to learn more about acute drug-induced liver injury
    Paul B Watkins
    Hamner Center for Drug Safety Sciences, University of North Carolina, Chapel Hill, NC, USA
    Hepatology 48:1680-9. 2008
    ....
  23. pmc Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans
    Alison H Harrill
    Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599, USA
    Genome Res 19:1507-15. 2009
    ..These studies demonstrate that a diverse mouse population can be used to understand and predict adverse toxicity in heterogeneous human populations through guided resequencing...
  24. pmc Acetaminophen dosing of humans results in blood transcriptome and metabolome changes consistent with impaired oxidative phosphorylation
    Rick D Fannin
    National Institute of Environmental Health Sciences Microarray Group, National Institutes of Health NIH, Research Triangle Park, NC 27709, USA
    Hepatology 51:227-36. 2010
    ..The timing of the changes and the correlation with NAPQI production are consistent with mechanisms known to underlie APAP hepatoxicity. These studies support the further exploration of the blood transcriptome for biomarkers of DILI...
  25. ncbi request reprint Liver transplantation for acute liver failure from drug induced liver injury in the United States
    Mark W Russo
    Division of Gastroenterology and Hepatology, Department of Medicine and Center for Gastrointestinal Biology and Diseases, University of North Carolina, Chapel Hill, NC 27599 7080, USA
    Liver Transpl 10:1018-23. 2004
    ..The increased frequency of African-American women undergoing liver transplantation for non-APAP drug induced liver injury warrants further study...
  26. pmc Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges
    Russell A Wilke
    Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA
    Nat Rev Drug Discov 6:904-16. 2007
    ..Key challenges for the discovery of predictive risk alleles for these SADRs are also considered...
  27. ncbi request reprint Differential inhibition of rat and human Na+-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1)by bosentan: a mechanism for species differences in hepatotoxicity
    Elaine M Leslie
    School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 7360, USA
    J Pharmacol Exp Ther 321:1170-8. 2007
    ..In conclusion, differential inhibition of Ntcp and NTCP may represent a novel mechanism for species differences in bosentan-induced hepatotoxicity...
  28. doi request reprint The Environmental Polymorphisms Registry: a DNA resource to study genetic susceptibility loci
    Patricia C Chulada
    Clinical Research Program, National Institute of Environmental Health Sciences, 111 T W Alexander Drive, Research Triangle Park, NC 27709, USA
    Hum Genet 123:207-14. 2008
    ..The success of the EPR based on the number of subjects recruited and genetic studies underway, suggests that it will be a model for future DNA resources...
  29. ncbi request reprint The influence of CYP3A5 expression on the extent of hepatic CYP3A inhibition is substrate-dependent: an in vitro-in vivo evaluation
    Nina Isoherranen
    Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA
    Drug Metab Dispos 36:146-54. 2008
    ..In conclusion, the effect of CYP3A5 on hepatic CYP3A-mediated inhibitory drug-drug interactions is substrate-dependent, and HLM, rather than rCYP3A, are the preferred in vitro system for predicting these interactions in vivo...
  30. ncbi request reprint 6'7'-Dihydroxybergamottin contributes to the grapefruit juice effect
    Shefali M Kakar
    Department of Pharmacology, University of Michigan, Ann Arbor, USA
    Clin Pharmacol Ther 75:569-79. 2004
    ..Our objective was to assess the contribution of 6',7'-dihydroxybergamottin (DHB) to the inhibitory effect of grapefruit juice toward intestinal cytochrome P450 (CYP) 3A4...
  31. ncbi request reprint Insight into hepatotoxicity: The troglitazone experience
    Paul B Watkins
    Hepatology 41:229-30. 2005
  32. ncbi request reprint Intestinal and hepatic CYP3A4 catalyze hydroxylation of 1alpha,25-dihydroxyvitamin D(3): implications for drug-induced osteomalacia
    Yang Xu
    Department of Pharmaceutics, Box 357610, University of Washington, Seattle, WA 98195 7610, USA
    Mol Pharmacol 69:56-65. 2006
    ..These and other data suggest that induction of CYP3A4-dependent 1,25(OH)(2)D(3) metabolism by antiepileptic drugs and other PXR ligands may diminish intestinal effects of the hormone and contribute to osteomalacia...
  33. ncbi request reprint Did this drug cause my patient's hepatitis?
    Neil Kaplowitz
    Ann Intern Med 138:159-60; author reply 159-60. 2003
  34. pmc Is quinine a suitable probe to assess the hepatic drug-metabolizing enzyme CYP3A4?
    Sompon Wanwimolruk
    College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA
    Br J Clin Pharmacol 54:643-51. 2002
    ..To evaluate the antimalarial agent quinine as a potential in vivo probe for hepatic cytochrome P450 (CYP) 3A4 activity...
  35. ncbi request reprint Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction
    Wei C Lau
    Department of Anesthesiology, University of Michigan, Ann Arbor, USA
    Circulation 107:32-7. 2003
    ..Because atorvastatin is metabolized by cytochrome P450 (CYP) 3A4, we hypothesized that clopidogrel might be activated by CYP3A4...
  36. ncbi request reprint Cytochrome P450 3A4 and P-glycoprotein mediate the interaction between an oral erythromycin breath test and rifampin
    Mary F Paine
    Department of Pharmacology, University of Michigan, Ann Arbor, USA
    Clin Pharmacol Ther 72:524-35. 2002
    ..Accordingly, we evaluated an oral stable-labeled ((13)C) formulation of the test (ERMBT(oral)) as an alternative CYP3A4 phenotyping probe...
  37. ncbi request reprint Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance
    Wei C Lau
    Department of Anesthesiology, University of Michigan Health System, 1G323 University Hospital, Box 0048, 1500 East Medical Center Drive, Ann Arbor, MI 48109 0048, USA
    Circulation 109:166-71. 2004
    ..Because the prodrug clopidogrel is activated by hepatic cytochrome P450 (CYP) 3A4, we hypothesized that interindividual variability in clopidogrel efficacy might be related to interindividual differences in CYP3A4 metabolic activity...
  38. ncbi request reprint Role of cytochrome P450 phenotyping in cancer treatment
    E Claire Dees
    J Clin Oncol 23:1053-5. 2005
  39. ncbi request reprint Increased CYP3A4 copy number in TONG/HCC cells but not in DNA from other humans
    Jatinder K Lamba
    Department of Pharmaceutical Sciences, St Jude Children s Research Hospital, Memphis, TN 38105, USA
    Pharmacogenet Genomics 16:415-27. 2006
    ..Tumors with increased CYP3A copy number (via amplification or increased chromosome 7q) would be expected to show reduced cytotoxicity to some chemotherapeutic drugs and potentially an increase in the outgrowth of drug resistant tumors...
  40. ncbi request reprint Are patients with elevated liver tests at increased risk of drug-induced liver injury?
    Mark W Russo
    Gastroenterology 126:1477-80. 2004
  41. doi request reprint Drug-induced liver injury network
    Paul B Watkins
    Am J Gastroenterol 103:1574-5. 2008
  42. ncbi request reprint CYP3A probes can quantitatively predict the in vivo kinetics of other CYP3A substrates and can accurately assess CYP3A induction and inhibition
    Evan D Kharasch
    University of Washington School of Medicine, Seattle, WA 98195, USA
    Mol Interv 5:151-3. 2005
    ..Recently, Benet has written on the futility of such an enterprise; however, other researchers believe the identification of valuable predictive probes is not only possible but crucial...
  43. ncbi request reprint Tolcapone: an efficacy and safety review (2007)
    C Warren Olanow
    Department of Neurology, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, NY 10029, USA
    Clin Neuropharmacol 30:287-94. 2007
    ..In addition, patients must be taken off the drug if blood tests show enzyme elevation of greater than twice the upper limit of normal. This article reviews the data pertaining to the safety and efficacy of tolcapone...
  44. ncbi request reprint MDR1 genotype is associated with hepatic cytochrome P450 3A4 basal and induction phenotype
    Jatinder Lamba
    Department of Pharmaceutical Sciences, St Jude Children s Research Hospital, Memphis, TN 38105, USA
    Clin Pharmacol Ther 79:325-38. 2006
    ..This study investigated whether common single-nucleotide polymorphisms (SNPs) in multidrug resistance 1 (MDR1), encoding P-glycoprotein, or the pregnane X receptor (PXR) were associated with basal or inducible CYP3A4 expression...
  45. pmc Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia
    Changcheng Zhou
    Department of Pharmaceutics, University of Washington, Seattle, Washington 98195 7610, USA
    J Clin Invest 116:1703-12. 2006
    ....
  46. ncbi request reprint Growth hormone secretion pattern is an independent regulator of growth hormone actions in humans
    Craig A Jaffe
    Divisions of Endocrinology and Metabolism, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
    Am J Physiol Endocrinol Metab 283:E1008-15. 2002
    ..Gender differences in drug metabolism and, potentially, gender differences in growth rate may be explained by sex-specific GH secretion patterns...

Research Grants16

  1. Hepatoxicity Clincal Research Network
    Paul Watkins; Fiscal Year: 2007
    ..We anticipate that our proposed infrastructure will allow successful identification and enrollment of patients experiencing severe DILl within the mid-Atlantic region of the country. ..
  2. FURANOCOUMARINS AND DRUGS EFFECT ON CYP3A4
    Paul Watkins; Fiscal Year: 2007
    ..abstract_text> ..
  3. GENERAL CLINICAL RESEARCH CENTERS ANNUAL MEETING
    Paul Watkins; Fiscal Year: 2006
    ..abstract_text> ..