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  • Wilkinson, G. R.  (5)
  • Pharmacy  (5)
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  • Pharmacy  (5)
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  • 1
    Online Resource
    Online Resource
    Biological determinants of propranolol disposition in man
    Wiley ; 1978
    In:  Clinical Pharmacology & Therapeutics Vol. 23, No. 2 ( 1978-02), p. 165-174
    Details
    In: Clinical Pharmacology & Therapeutics, Wiley, Vol. 23, No. 2 ( 1978-02), p. 165-174
    Abstract: Propranolol disposition has been investigated in 15 normal subjects with the use of a protocol which allowed simultaneous determination of the kinetics of the drug after both intravenous and oral administration by giving H 3 ‐propranolol intravenously and native drug orally. In addition, plasma propranolol binding and the bloodlplasma propranolol concentration ratio (B/P) were measured. The data were used to calculate hepatic blood flow as well as systemic drug clearance from the blood and intrinsic clearance, which is an estimate of the activity of the drug‐metabolizing enzymes. Under the steady‐state conditions used, the hepatic extraction ratio was found to be 64% ± 2.5% (mean ± SE) resulting in a bioavailability of 36% ± 2.6%. Calculated liver blood flow varied from 778 to 2,162 ml/min, and, as predicted, the systemic clearance of propranolol (0.61 to 1.52 L/min) was correlated with both liver blood flow and intrinsic drug clearance (1.16 to 5.08 L/min). Variations in plasma drug binding had no effect on systemic clearance. Because of presystemic or “first‐pass” elimination, the variation in both free and total propranolol levels was greater after oral (5‐fold) than intravenous administration (2.5‐fold). We conclude that the approach described allows quantification of all of the biological determinants of propranolol disposition in subjects with normal hepatic vasculature.
    Type of Medium: Online Resource
    ISSN: 0009-9236 , 1532-6535
    URL: Issue
    URL: Article
    DOI: 10.1002/cpt.1978.23.issue-2
    DOI: 10.1002/cpt1978232165
    RVK:
    XA 36900
    Language: English
    Publisher: Wiley
    Publication Date: 1978
    detail.hit.zdb_id: 2040184-X
    detail.hit.zdb_id: 123793-7
    SSG: 15,3
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Effects of age and cigarette smoking on propranolol disposition
    Wiley ; 1979
    In:  Clinical Pharmacology & Therapeutics Vol. 26, No. 1 ( 1979-07), p. 8-15
    Details
    In: Clinical Pharmacology & Therapeutics, Wiley, Vol. 26, No. 1 ( 1979-07), p. 8-15
    Abstract: The effects of age and cigarette smoking on the disposition of propranolol have been investigated in 27 normal men, aged 21 to 73 yr. The drug was administered orally (80 mg) every 8 hr and 40 µCi intravenous 3 H‐propranolol were administered simultaneously with the seventh dose. Labeled and unlabeled propranolol concentrations were determined in serial blood samples obtained over the next 8 hr. Subgrouping the oral blood concentration/time data according to age (younger or older than 35 yr) showed that the mean levels in the older group were as much as twofold those in the younger group, and that the terminal half‐life (t½β) was prolonged with age (4.19 ± 1.38 vs. 5.05 ± l.36 hr, mean ± SD; p = 0.03). Substratification of cigarette smokers ( 〉 10 cigarettes daily) from nonsmokers indicated that the mean levels in the nonsmokers were 200% higher but there was no t½β difference. Despite the considerable interindividual variability, there was a trend for the weight‐normalized, average steady‐state levels to be lower in smokers than in nonsmokers, with the difference becoming smaller with increasing age. Analysis of the data indicated that the intrinsic total clearance of propranolol decreased with age only in the smokers, and toward the constant value of the nonsmokers, while apparent liver blood flow declined equally with age in both groups. Consequently, systemic‐clearance correlated negatively with age in the smokers and in the group as a whole. No age relationships were found in the volume of distribution and, thus, correlations of age and t½β were of the same order as those of systemic clearance. No changes were observed in systemic availability or plasma binding with aging in either group. It, therefore, appears that cigarette smoking habits are important in the altered steady‐state kinetics of propranolol that develops with aging. The results are consistent with a decreased induction of drug‐metabolizing enzyme with aging.
    Type of Medium: Online Resource
    ISSN: 0009-9236 , 1532-6535
    URL: Issue
    URL: Article
    DOI: 10.1002/cpt.1979.26.issue-1
    DOI: 10.1002/cpt19792618
    RVK:
    XA 36900
    Language: English
    Publisher: Wiley
    Publication Date: 1979
    detail.hit.zdb_id: 2040184-X
    detail.hit.zdb_id: 123793-7
    SSG: 15,3
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Effect of aging and cigarette smoking on antipyrine and indocyanine green elimination
    Wiley ; 1979
    In:  Clinical Pharmacology & Therapeutics Vol. 26, No. 1 ( 1979-07), p. 16-20
    Details
    In: Clinical Pharmacology & Therapeutics, Wiley, Vol. 26, No. 1 ( 1979-07), p. 16-20
    Abstract: The plasma clearances of antipyrine (AP) and indocyanine green (ICG) have been measured after intravenous administration in each of 20 normal male subjects aged 22 to 72 yr. An additional 4 subjects aged 65 to 73 yr received only ICG. AP clearance fell with age in the group as a whole (r = 0.56; p 〈 0.01), but when cigarette smoking habits were considered the relationship was apparent only in smokers (r = 0.68; p 〈 0.02). In the under 40 yr group, AP clearance was higher in smokers than nonsmokers (p 〈 0.02). There was no such difference in men over 40 yr of age. These observations suggest that the enzyme‐inducing effect of smoking diminishes with advancing years. In contrast, and consistent with a reduction in liver blood flow, the clearance of the highly extracted ICG fell with age, irrespective of smoking habits (r = 0.57; p 〈 0.004). These findings suggest that while hepatic drug clearance may be impaired in elderly people, the outcome depends not only on the effects of the aging process on the physiologic determinants of hepatic clearance (liver blood flow and the activity of the drug‐metabolizing enzymes) but also on the effects of environmental factors, such as smoking.
    Type of Medium: Online Resource
    ISSN: 0009-9236 , 1532-6535
    URL: Issue
    URL: Article
    DOI: 10.1002/cpt.1979.26.issue-1
    DOI: 10.1002/cpt197926116
    RVK:
    XA 36900
    Language: English
    Publisher: Wiley
    Publication Date: 1979
    detail.hit.zdb_id: 2040184-X
    detail.hit.zdb_id: 123793-7
    SSG: 15,3
    Location Call Number Limitation Availability
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Plasma binding and disposition of furosemide in the nephrotic syndrome and in uremia
    Wiley ; 1978
    In:  Clinical Pharmacology & Therapeutics Vol. 24, No. 2 ( 1978-08), p. 199-207
    Details
    In: Clinical Pharmacology & Therapeutics, Wiley, Vol. 24, No. 2 ( 1978-08), p. 199-207
    Abstract: The pharmacokinetic disposition of furosemide has been investigated in six normal subjects, 7 patients with the nephrotic syndrome and 6 patients with uremia. Furosemide levels were measured using a specific HPLC analytical procedure and protein binding was measured by equilibrium dialysis using 3 H‐furosemide. The high binding offurosemide in normal subjects (95.9 ± 0.1%) was reduced in both uremia (94.4 ± 0.4%) and the nephrotic syndrome (93.2 ± 0.5%). When alt three study groups were combined, furosemide binding correlated with the serum albumin concentration measured in each subject at the time of the study (r = −0.83, p 〈 0.001). Approximately 50% of the systemic clearance of total drug in controls (158 ± 11 ml/min) was due to renal clearance. The renal clearance of total furosemide in the nephrotic syndrome was not altered, but renal clearance of unbound drug decreased in proportion to the creatinine clearance. Extrarenal clearance was unaffected in the nephrotic syndrome. In contrast, in uremia, both renal and extrarenal clearances were significantly reduced. The fall in renal clearance was consistent with a reduction in functioning nephrons and the presence of competitive inhibitors for tubular secretion. The volume of distribution offurosemide at steady‐state correlated with both serum albumin (r= +0.73, p 〈 0.001) and drug binding (r = +0.63, p 〈 0.005) and was increased in the nephrotic syndrome. Furosemide half‐life was unchanged in nephrotic syndrome but prolonged by threefold in uremia. Chronic hemodialysis for two to four months in 4 of the uremic subjects produced no significant change in any pharmacokinetic parameter. This study indicates that the disposition of furosemide is not only dependent on renal function but also on the serum albumin concentration.
    Type of Medium: Online Resource
    ISSN: 0009-9236 , 1532-6535
    URL: Issue
    URL: Article
    DOI: 10.1002/cpt.1978.24.issue-2
    DOI: 10.1002/cpt1978242199
    RVK:
    XA 36900
    Language: English
    Publisher: Wiley
    Publication Date: 1978
    detail.hit.zdb_id: 2040184-X
    detail.hit.zdb_id: 123793-7
    SSG: 15,3
    Location Call Number Limitation Availability
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    Online Resource
  • 5
    Online Resource
    Online Resource
    The Influence of Cirrhosis on Steady-State Blood Concentrations of Unbound Propranolol after Oral Administration1
    Springer Science and Business Media LLC ; 1978
    In:  Clinical Pharmacokinetics Vol. 3, No. 6 ( 1978), p. 478-487
    Details
    In: Clinical Pharmacokinetics, Springer Science and Business Media LLC, Vol. 3, No. 6 ( 1978), p. 478-487
    Type of Medium: Online Resource
    ISSN: 0312-5963
    URL: Article
    DOI: 10.2165/00003088-197803060-00005
    RVK:
    XA 36894
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 1978
    detail.hit.zdb_id: 197627-8
    SSG: 15,3
    Location Call Number Limitation Availability
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    Online Resource
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