摘要:

The relative contributions of the debrisoquin and mephenytoin isozymes of hepatic cytochrome P‐450 to the stereoselective metabolism of propranolol have been studied in a panel of volunteers of known oxidative phenotypes. Six subjects were extensive metabolizers of both debrisoquin and mephenytoin (EM). Four subjects were poor metabolizers of debrisoquin but rapid for mephenytoin (PMD). Five subjects were poor metabolizers of mephenytoin but rapid for debrisoquin (PMM), and one individual had a deficiency for both test compounds (PMD/M). Partial metabolic clearances of each propranolol enantiomer to 4‐hydroxypropranolol (4‐OH‐P), the sulfate, and glucuronide conjugates of 4‐OH‐P, naphthoxylactic acid (NLA) and propranolol glucuronide, were estimated after a single oral dose of racemic propranolol (80 mg). The partial metabolic clearance of both enantiomers to total 4‐OH‐P in the PMDgroup was 75% less than in the EM and PMMgroups, indicating the contribution of the debrisoquin isozyme to this route of metabolism. The R/S ratios for the clearance to 4‐OH‐P were similar between EM and PMD(2.5 ± 0.5 vs 2.5 ± 0.4, respectively), implying that the different enzymes involved in ring hydroxylation (i.e., the debrisoquin isozyme and other hydroxylases) have similar stereoselective preferences. The partial metabolic clearance to NLA was 55% less in the PMMgroup than in the EM and PMDgroups, indicating that S‐mephenytoin 4‐hydroxylase contributes to the metabolic conversion of propranolol to NLA. The R/S ratios for the clearance to NLA were close to unity in all groups. The partial metabolic clearance to propranolol glucuronide also did not exhibit stereoselectivity and was similar in all groups. The one subject with deficiencies in both debrisoquin and S‐mephenytoin hydroxylase activities had reduced partial clearances of both 4‐OH‐P and NLA and was the only individual to have a reduced total propranolol clearance. Thus two independent isozymes of cytochrome P‐450, previously identified as being responsible for debrisoquin and S‐mephenytoin hydroxylation, contribute to the two separate oxidative routes of metabolism of propranolol. Deficiencies of both routes result in impaired total clearance of propranolol.Clinical Pharmacology and Therapeutics(198

ISSN:0009-9236    

DOI:10.1038/clpt.1989.11

年代:1989

数据来源: WILEY

摘要:

Plasma adenosine levels in five healthy volunteers for 5 consecutive days showed far less intrasubject than intersubject variation(p<0.0001), indicating that plasma adenosine levels are relatively constant during this period. Plasma adenosine levels were then measured in a different group of five healthy subjects for a 5‐day control period and during a 5‐day course of oral dipyridamole at a dose of 100 mg every 6 hours. Intrasubject comparisons showed that plasma adenosine levels were significantly higher during the 5 days of dipyridamole administration than during the control period(p= 0.017) and that this increase was most significant after 48 hours of drug(p<0.001) administration. The average increase was 0.133 µmol/L (60%) with a range of 0.063 to 0.197 µmol/L (37% to 212%) during the last 3 days. A significant positive correlation was noted between plasma adenosine and dipyridamole levels(p= 0.001). We conclude that adenosine levels are relatively stable for an individual and are maximally increased after 2 days of oral dipyridamole.Clinical Pharmacology and Therapeutics(1989)45,80–84; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1989.12

年代:1989

数据来源: WILEY

摘要:

Enoximone is an investigational cardiotonic agent with positive inotropic and vasodilatory properties. In this protocol the effects of enoximone on parameters of renal function in patients(n= 14) with New York Heart Association class II or III congestive heart failure were determined after intravenous (IV) treatment (2 mg/kg) and after chronic oral administration (150 mg t.i.d.), either alone or with added furosemide (40 mg b.i.d.). Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), filtration fraction, mean arterial pressure (MAP), renal blood flow (RBF), and renal vascular resistance (RVR) were determined each time. Plasma volume (PV) was determined at baseline and after oral enoximone and after oral enoximone plus furosemide. Significant reductions in GFR (18%) and ERPF (20%) were observed after IV treatment but not after oral treatment with or without furosemide. MAP also was lowered significantly by 14% after IV administration but not after oral treatments. PV after oral enoximone plus furosemide was reduced significantly (31%) compared with baseline. These results demonstrate that enoximone produces acute reductions in GFR and ERPF when given intravenously but has no effect on parameters of renal function when given orally, either alone or with furosemide.Clinical Pharmacology and Therapeutics(1989)45,85–91; doi:10.1038/clpt.1989.

ISSN:0009-9236    

DOI:10.1038/clpt.1989.13

年代:1989

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1989)45,92–94; doi:10.1038/clpt.1989.

ISSN:0009-9236    

DOI:10.1038/clpt.1989.14

年代:1989

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1989)45,95–95; doi:10.1038/clpt.1989.

ISSN:0009-9236    

DOI:10.1038/clpt.1989.15

年代:1989

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1989)45,96–120; doi:10.1038/clpt.1989.

ISSN:0009-9236    

DOI:10.1038/clpt.1989.16

年代:1989

数据来源: WILEY