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Dive into the research topics where Robert J. Herman is active.

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Featured researches published by Robert J. Herman.


Clinical Pharmacology & Therapeutics | 1989

Disposition of lorazepam in human beings: Enterohepatic recirculation and first‐pass effect

Robert J. Herman; J Duc Van Pham; Cameron B. Szakacs

The effects of neomycin and cholestyramine on the disposition of lorazepam was examined in seven healthy drug‐free men. Half‐life as determined for the oral route was, in all subjects, 15% to 35% less than that determined for the intravenous route. Free oral clearance was slightly but not significantly less than free systemic clearance, but the ratio of the AUC of lorazepam glucuronide corrected for dose was twofold greater by the oral route. Urinary recoveries also differed (71.6% and 50.4%, oral versus intravenous). Neomycin and cholestyramine treatment resulted in a 19% to 26% reduction in half‐life attendant on a 34% increase in free oral clearance and a 24% increase in free systemic clearance. This suggests that lorazepam undergoes significant enterohepatic recirculation in human beings and that there exists an extrahepatic pathway, at least for the intravenous route. Since pharmacokinetic measurements do not take these physiologic processes into account, the drug cannot properly be used as a marker of conjugative metabolism.


European Journal of Clinical Pharmacology | 1990

Sex-difference and the effects of smoking and oral contraceptive steroids on the kinetics of diflunisal

J. I. Macdonald; Robert J. Herman; Roger K. Verbeeck

SummaryThe single dose pharmacokinetics of diflunisal were studied in 4 groups of 6 young volunteers: control men, control women, women taking low estrogen oral contraceptive steroids (OCS), and women smokers (10–20 cigarettes/day).The plasma clearance of diflunisal was significantly higher in men (0.169 ml·min−1·kg−1) and in women on OCS (0.165 ml·min−1·kg−1) as compared to control women (0.108 ml·min−1·kg−1). Partial metabolic clearances of diflunisal by the three conjugative pathways (phenolic and acyl glucuronide formation, sulphate conjugation) were all increased in men and women OCS users as compared to control women. Statistically significant increases, however, were only observed for the partial metabolic clearance of diflunisal by phenolic glucuronidation between men and women (2.91 vs. 1.85 ml·min−1 respectively), and for the partial clearance by acyl glucuronidation between OCS users and control women (4.81 vs. 3.01 ml·min−1 respectively).Smoking resulted in a moderate increase (35%) in plasma diflunisal clearance. However, a significant reduction in total urinary recovery of diflunisal and its glucuronide and sulphate conjugates was found in smokers (70.5% in smokers as compared to 84.2–87.2% in the 3 other study groups). Consequently, smoking may have induced hydroxylation, a minor oxidative metabolic pathway of diflunisal recently discovered in man.


The Journal of Clinical Pharmacology | 1994

Disposition of Lorazepam in Gilbert's Syndrome: Effects of Fasting, Feeding, and Enterohepatic Circulation

Robert J. Herman; Archana Chaudhary; Cameron B. Szakacs

The effects of fasting and feeding of a high‐carbohydrate, low‐fat diet on the glucuronidation and enterohepatic circulation (EHC) of lorazepam were examined in seven healthy men (age 18–30 years) and seven matched patients with Gilberts syndrome. A simultaneous intravenous/oral dosing regimen was used, with half of each group receiving treatment with neomycin and cholestyramine (neo/chol) to block the EHC of the drug. Feeding increased the clearance of free lorazepam from 10.96 ± 0.56 (mean ± SD) to 14.11 ± 1.21 mL/min/kg (P = 0.05) in patients with Gilberts syndrome when examined in the presence of neo/chol. Clearances, on the other hand, decreased with feeding in control Gilberts patients (7.61 ± 0.54 versus 8.82 ± 0.48 mL/min/kg), although the differences were not significant (P = 0.09). In contrast to both of these groups, feeding decreased lorazepam clearances (13.33 ± 0.32 to 12.45 ± 0.52 mL/min/kg, P = 0.17) in neo/chol‐treated normals and increased clearances (9.95 ± 1.84 to 12.38 ± 2.05 mL/min/kg, P = 0.04) in control normals. Lorazepam clearances were also 20–40% lower in patients with Gilberts syndrome compared with normals when studied fasting and with neo/chol, or fed and in the control state (P < 0.05 for both). Thus, the glucuronidation and EHC of lorazepam is sensitive both to diet and to the presence or absence of the Gilberts trait.


Diabetes | 1994

High Glucose Attenuates Peptide Agonist-Evoked Increases in Cytosolic Free [Ca2+] in Rat Aortic Smooth Muscle Cells

Lakshman Sandirasegarane; Robert J. Herman; Venkat Gopalakrishnan

Incubation of cultured rat aortic smooth muscle cells (ASMCs) in a medium containing high glucose concentrations (25 mM) did not affect the basal cytosolic free calcium ([Ca2+]i) but led to significant reductions in peak [Ca2+]i response evoked by arginine vasopressin, angiotensin II, and endothelin-1 (ET-1). This was observed in both the presence and absence of extracellular Ca2+. Maintenance of rat ASMCs in a medium containing mannose (an osmotic control for high glucose) did not affect either the basal or peptide agonist-evoked increase in [Ca2+]i. However, pretreatment with either the nonselective protein kinase C (PKC) inhibitor staurosporine or the selective PKC inhibitor 2,6-diamino-N-([1-(1-oxotridecyl)-2 piperidinyl] methyl) hexanamide reversed the attenuating effect of high glucose on peak [Ca2+]i response evoked by ET-1. Also, short-term incubation of ASMCs with the active phorbol ester, phorbol 12-myristate 13-acetate, led to a reduction in peak [Ca2+]i response to all three agonists, whereas the inactive phorbol ester, 4α-phorbol 12,13-didecanoate, which does not activate PKC, had no such effect. Although high-glucose treatment of rat ASMCs led to significant reductions in the maximal number of binding sites to the extent of 39% of [125I]ET-1 specific binding, no significant differences in the affinity (Kd ∼110 pM) characteristics were evident between control and high-glucose treatment groups. It is proposed that incubation of rat ASMCs with high glucose enhances the de novo synthesis of diacylglycerol and activates membrane-bound PKC and that this, in turn, impairs agonist-mediated intracellular Ca2+ mobilization.


European Journal of Clinical Pharmacology | 1995

Effect of probenecid on the formation and elimination kinetics of the sulphate and glucuronide conjugates of diflunisal.

J. I. Macdonald; Sylvia M. Wallace; Robert J. Herman; Roger K. Verbeeck

The effect of probenecid on the pharmacokinetics of diflunisal and its glucuronide and sulphate conjugates was studied in 8 healthy volunteers. Diflunisal 250 mg b. d. was administered p. o. for 15 days and its steady state pharmacokinetics was evaluated on Day 16 after the last dose (control phase). Probenecid 500 mg b. d. was co-administered throughout the entire study period in the treatment phase of the study.The steady state plasma concentration of diflunisal was significantly higher during the probenecid treatment phase as compared to the control phase (104.0 vs. 63.1 μg·ml−1). This was the result of a significant decrease in the plasma clearance of diflunisal from 5.8 (control) to 3.4 ml·min−1 (probenecid co-administration). The metabolite formation clearances of both glucuronides were significantly decreased by probenecid, -45 % and -54 % for the phenolic and acyl glucuronide, respectively. The metabolite formation clearance of the sulphate conjugate was not affected by probenecid co-administration.Steady state plasma concentrations of the sulphate and glucuronide conjugates of diflunisal were 2.5- to 3.1-fold higher during probenecid co-administration, due to a significant reduction in the renal clearance of the three diflunisal conjugates. Probenecid also reduced the plasma protein binding of diflunisal, but only to a minor extent; the unbound plasma fraction of diflunisal at steady state averaged between 5 and 30 % higher during probenecid co-administration.


Clinical Pharmacology & Therapeutics | 1996

Prevalence and Incidence of Cough in Patients on Treatment with Angiotensin Converting Enzyme Inhibitors (ACE‐I)

Robert J. Herman; George Pylypchuk; B.L. Evans

Clinical Pharmacology & Therapeutics (1996) 59, 139–139; doi: 10.1038/sj.clpt.1996.57


British Journal of Clinical Pharmacology | 1988

Effect of dose on the glucuronidation and sulphation kinetics of diflunisal in man: single dose studies.

Gr Loewen; Robert J. Herman; Sg Ross; Roger K. Verbeeck


British Journal of Clinical Pharmacology | 1996

Disposition of diazepam in young and elderly subjects after acute and chronic dosing

Robert J. Herman; Grant R. Wilkinson


British Journal of Clinical Pharmacology | 1990

The effect of multiple dosage on the kinetics of glucuronidation and sulphation of diflunisal in man.

Roger K. Verbeeck; Gr Loewen; J. I. Macdonald; Robert J. Herman


Pharmaceutical Research | 1991

In Vitro Binding of Lorazepam and Lorazepam Glucuronide to Cholestyramine, Colestipol, and Activated Charcoal

Robert J. Herman; Archana Chaudhary

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Roger K. Verbeeck

Université catholique de Louvain

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J. I. Macdonald

University of Saskatchewan

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Archana Chaudhary

University of Saskatchewan

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Gr Loewen

University of Saskatchewan

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B.L. Evans

University of Saskatchewan

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J Duc Van Pham

University of Saskatchewan

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