MA Bruce

Wake Forest School of Medicine, Winston-Salem, North Carolina, United States

Are you MA Bruce?

Claim your profile

Publications (6)42.77 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The relative susceptibility of intestinal and hepatic cytochrome P450 (CYP) 3A to induction by rifampin (INN, rifampicin), as a function of age and sex, was investigated with the CYP3A substrate midazolam. Fourteen young women (mean age, 26 +/- 4 years), 14 young men (mean age, 27 +/- 4 years), 14 elderly women (mean age, 72 +/- 5 years), and 10 elderly men (mean age, 70 +/- 4 years) received simultaneous intravenous doses (0.05 mg/kg over a 30-minute period) and oral doses of midazolam (3-8 mg of a stable isotope, (15)N(3)-midazolam) before and after 7 days of rifampin dosing (600 mg once daily in the evening). Serum and urine samples were assayed for midazolam, (15)N(3)-midazolam, and metabolites by liquid chromatography-mass spectrometry. No significant difference (P > or =.05) in the baseline systemic and oral clearance of midazolam was observed between male and female or young and old volunteers. Rifampin significantly (P <.0001) increased the systemic and oral clearance of midazolam from 0.44 +/- 0.2 L. h/kg and 1.56 +/- 0.8 L x h/kg to 0.96 +/- 0.3 L x h/kg and 34.4 +/- 21.2 L x h/kg, respectively. Likewise, the oral clearance of midazolam was significantly (P <.0001) increased in women and men, from 1.64 +/- 0.87 L x kg/h and 1.46 +/- 0.7 L x kg/h to 28.4 +/- 13.2 L x kg/h and 41.6 +/- 26.5 L x kg/h, respectively. A significant (P =.0023) effect of sex was noted in the extent of induction of the oral clearance of midazolam, being greater in men than in women. In contrast, the extent of midazolam systemic clearance induction was greater in women than in men (P =.0107). Age did not influence the extent of intestinal and hepatic CYP3A induction as determined by the oral and systemic clearance of midazolam. Rifampin dosing significantly (P <.0001) reduced the oral availability by 88%, from 0.32 +/- 0.13 to 0.04 +/- 0.02. Correspondingly, hepatic and intestinal availabilities were significantly (P <.0001) reduced after rifampin administration. After rifampin, the correlation coefficient for the relationship between oral availability and intestinal availability was significantly (P <.0001) reduced from 0.96 to 0.67, which reflects the increasing contribution of hepatic extraction to the determination of midazolam oral availability. A significant nonlinear inverse relationship was observed between the percent change in systemic clearance of midazolam and the initial baseline midazolam systemic clearance (r = -0.68, N = 52, P <.0001). Likewise, a significant inverse relationship was observed between the percent change in oral clearance and the baseline oral clearance (r = -0.39, N = 52, P =.0041). A significant inverse relationship between the ratio of hepatic intrinsic clearance in the presence of rifampin to that in the absence of rifampin and the corresponding ratio of intestinal intrinsic clearance was observed (Spearman correlation coefficient [r] = -0.68, P <.0001) and indicates that in a given individual the extent of induction was high at either the hepatic or the intestinal site but not both. Sex-related differences exist in the extent of intestinal and hepatic CYP3A induction by rifampin. The extent of induction at hepatic and intestinal sites was inversely dependent and reflected the independent regulation of CYP3A expression at these sites. The large interindividual variation in the extent of induction is explained in part by the variation in baseline expression of CYP3A. Sex-related differences in response to CYP3A inducers will be substrate-dependent and reflect the relative contribution of hepatic and intestinal sites of metabolism.
    Clinical Pharmacology &#38 Therapeutics 09/2003; 74(3):275-87. DOI:10.1016/S0009-9236(03)00187-5 · 7.90 Impact Factor
  • M A Bruce · S D Hall · B D Haehner-Daniels · J C Gorski ·
    [Show abstract] [Hide abstract]
    ABSTRACT: The in vivo effects of oral clarithromycin administration on the in vivo activity of cytochrome P450 1A2, 2C9, and 2D6 were determined. The cytochrome P450 probes caffeine (CYP1A2), tolbutamide (CYP2C9), and dextromethorphan (CYP2D6) were administered as an oral cocktail prior to and 7 days after oral clarithromycin (500 mg twice daily) administration to 12 healthy male subjects. Blood and urine samples were collected and assayed for each of the compounds and their metabolites using high-performance liquid chromatography. The CYP1A2 indices, oral caffeine clearance (6.2 +/- 3.3 l/h before and 5.7 +/- 4.2 l/h after, p > 0.05) and the 6-h paraxanthine to caffeine serum concentration ratio (0.49 +/- 0.3 before and 0.44 +/- 0.3 after, p > 0.05), were unchanged following clarithromycin dosing. Neither the tolbutamide oral clearance (0.77 +/- 0.28 l/h before and 0.72 +/-0.24 l/h after, p > 0.05) nor the tolbutamide urinary metabolic ratio (779 +/- 294 before and 681 +/- 416 after, p > 0.05) indices of CYP2C9 were altered by clarithromycin administration. In the case of CYP2D6, the dextromethorphan to dextrorphan urinary ratio was not significantly different before (0.021 +/- 0.04) and after (0.024 +/- 0.06) clarithromycin dosing. In conclusion, clarithromycin does not appear to alter the in vivo catalytic activity of CYP1A2, CYP2C9, and CYP2D6 in healthy individuals as assessed by caffeine, tolbutamide, and dextromethorphan, respectively.
    Drug Metabolism and Disposition 07/2001; 29(7):1023-8. · 3.25 Impact Factor
  • MA Hamman · MA Bruce · B D Haehner-Daniels · S D Hall ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Our objective was to assess the effect of rifampin (INN, rifampicin) on the pharmacokinetics of fexofenadine and to assess the influence of advanced age and sex. Twelve young volunteers (6 men and 6 women; age range, 22 to 35 years) and twelve elderly volunteers (6 men and 6 women; age range, 65 to 76 years) received a 60-mg oral dose of fexofenadine before and after treatment with 600 mg of oral rifampin for 6 days. Blood and urine were collected for 48 hours and assayed for fexofenadine, azacyclonol, and rifampin by HPLC with either fluorescence or mass spectrometry detection. All of the groups had a significant increase (P <.05) in the oral clearance of fexofenadine after rifampin treatment: young men, 2955 +/- 1516 versus 5524 +/- 3410 mL/min; young women, 2632 +/- 996 versus 7091 +/- 5,379 mL/min; elderly men, 1760 +/- 850 versus 4608 +/- 1159 mL/min; and elderly women, 2210 +/- 554 versus 4845 +/- 1600 mL/min. The peak serum concentration of fexofenadine was also significantly reduced (P <.05) by rifampin treatment: young men, 77 +/- 31 versus 52 +/- 17 ng/mL; young women, 72 +/- 19 versus 36 +/- 14 ng/mL; elderly men, 106 +/- 42 versus 52 +/- 14 ng/mL; elderly women, 76 +/- 23 versus 46 +/- 19 ng/mL. Half-life (150 to 230 minutes), time to maximum concentration (130 to 205 minutes), renal clearance (95 to 153 mL/min), and fraction unbound (2.9% to 3.7%) of fexofenadine showed no significant difference between control and treatment. The amount of azacyclonol, a CYP3A4 mediated metabolite of fexofenadine, eliminated renally increased on average 2-fold after rifampin dosing; however, this pathway accounted for less than 0.5% of the dose. No effect of age or sex on fexofenadine disposition or serum trough rifampin concentration (0.2 microg/mL to 1.8 microg/mL) was observed before or after rifampin treatment. This study showed that rifampin effectively increased fexofenadine oral clearance and that this effect was independent of age and sex. We conclude that the cause of the increased oral clearance of fexofenadine is a reduced bioavailability caused by induction of intestinal P-glycoprotein.
    Clinical Pharmacology &#38 Therapeutics 04/2001; 69(3):114-21. DOI:10.1067/mcp.2001.113697 · 7.90 Impact Factor
  • MA Bruce · JC Gorski · Y. Liu · SD Hall · B. D. Haehner-Daniels ·

    Clinical Pharmacology &#38 Therapeutics 02/1999; 65(2):136-136. DOI:10.1016/S0009-9236(99)80078-2 · 7.90 Impact Factor

  • Clinical Pharmacology &#38 Therapeutics 02/1999; 65(2):136-136. DOI:10.1016/S0009-9236(99)80076-9 · 7.90 Impact Factor

  • Clinical Pharmacology &#38 Therapeutics 02/1999; 65(2):192-192. DOI:10.1016/S0009-9236(99)80298-7 · 7.90 Impact Factor

Publication Stats

301 Citations
42.77 Total Impact Points


  • 2003
    • Wake Forest School of Medicine
      Winston-Salem, North Carolina, United States
  • 2001
    • Indiana University-Purdue University School of Medicine
      • Division of Clinical Pharmacology
      Indianapolis, Indiana, United States
  • 1999
    • Indiana University-Purdue University Indianapolis
      • Division of Clinical Pharmacology
      Indianapolis, Indiana, United States