摘要:

Tolrestat is an aldose reductase inhibitor undergoing clinical trials in diabetic subjects that may reduce the severity of chronic tissue damage associated with hyperglycemia. These studies were conducted to evaluate the pharmacokinetics of tolrestat in healthy young and elderly male and female subjects and in young and elderly subjects with diabetes. The drug was administered in a multiple‐dose regimen, and steady‐state parameters were obtained. There were no important gender‐related differences, but mean values for apparent oral clearance, renal clearance, and corresponding unbound parameters were significantly lower for the elderly healthy subjects than for the young healthy subjects. The drug is highly bound to plasma proteins, and the unbound fraction (0.75%) did not differ among the subjects. The results from young and elderly diabetic subjects suggest that diabetes per se has no influence on tolrestat disposition but that there is an age‐related reduction in apparent oral clearance (30 versus 18 ml/hr/kg) and a corresponding increase in the minimum steady‐state plasma concentration (1.2 versus 1.9 μg/ml). These data indicate a possible need to reduce the dose of tolrestat in elderly subjects, assuming the same concentration‐response relationship.Clinical Pharmacology&Therapeutics(1996)59,

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90000-4

年代:1996

数据来源: WILEY

摘要:

Background and objectiveAntipyrine has been widely used as a probe drug for human oxidative drug metabolism. To evaluate the role of antipyrine as a model drug, we have identified the cytochrome P450 enzymes involved in 4‐hydroxyantipyrine, 3‐hydroxymethylantipyrine, and norantipyrine formation.MethodsWe used the following methods for this study: (1) determination of enzyme kinetics for antipyrine metabolite formation in human liver microsomes, (2) inhibition studies with antibodies and inhibitors, and (3) formation of metabolites by stable expressed human P450 enzymes.ResultsAntipyrine biotransformation could be described by Michaelis‐Menten kinetics:norantipyrine: maximum rate of metabolite formation (Vmax), 0.91 ± 0.04 nmol · mg−1· min−1; Michaelis‐Menten constant (Km), 19.0 ± 0.8 mmol/L;4‐hydroxyantipyrine: Vmax, 1.54 ± 0.08 nmol · mg−1· min−1; Km, 21.2 ± 0.4 mmol/L;3‐hydroxymethylantipyrine: Vmax, 0.83 ± 0.04 nmol · mg−1· min−1; Km, 39.6 ± 2.5 mmol/L. Antibodies against CYP3A4 inhibited the formation of 4‐hydroxyantipyrine by 25% to 65%. LKM‐2 antibodies (anti‐CYP2C) caused a 75% to 100% inhibition of norantipyrine and a 58% to 80% inhibition of 3‐hydroxymethylantipyrine formation. Sulfaphenazole inhibited the formation of 3‐hydroxymethylantipyrine and norantipyrine by about 50%. Furafylline and fluvoxamine inhibited norantipyrine, 4‐hydroxyantipyrine, and 3‐hydroxymethylantipyrine formation by about 30%, 30%, and 50%, respectively. Ketoconazole reduced formation of norantipyrine, 3‐hydroxymethylantipyrine, and 4‐hydroxyantipyrine by up to 80%. Formation in stable expressed enzymes indicated involvement of CYP1A2, CYP2B6, CYP2C, and CYP3A4 in metabolite formation.ConclusionAntipyrine metabolites are formed by at least six hepatic cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, and CYP3A4). 4‐Hydroxylation is mainly catalyzed by CYP3A4 and, to a lesser extent, by CYP1A2. The CYP2C subfamily contains the predominant enzymes for norantipyrine formation, and CYP1A2 is also involved. Formation of 3‐hydroxymethylantipyrine is mediated by CYP1A2 and CYP2C9. Because several cytochrome P450 enzymes are involved in the formation of each metabolite, antipyrine is not well suited as a probe for distinct human cytochrome P450 enzymes

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90001-6

年代:1996

数据来源: WILEY

摘要:

ObjectivesA number of caffeine metabolite ratios (CMRs) have been proposed to measure CYP1A2 activity in vivo. The effect of liver disease on these ratios is not clear. The objective of this study was to determine the influence of liver disease on caffeine metabolite ratios.Study designTwo studies were performed. First, in healthy control subjects and in subjects with cirrhosis, caffeine clearance was measured by intravenous infusion of stable isotope‐labeled caffeine while subjects consumed oral caffeine. Second, spot urine samples were collected from control subjects and from subjects with either chronic hepatitis or cirrhosis while they consumed caffeine.ResultsIn study 1, caffeine clearance was decreased in subjects with cirrhosis (control mean, 0.14 L/hr/kg; cirrhosis mean, 0.04 L/hr/kg;p= 0.003). CMRs were affected by liver disease (e.g., ratio characterizing paraxanthine demethylation [AAMU + 1X + 1U/17U], control median, 8.3; cirrhosis median, 6.2;p= 0.005). AAMU + 1X + 1U/17U correlated significantly with caffeine clearance in the control group (r2= 0.68;p= 0.001) and in subjects with cirrhosis (r2= 0.41;p= 0.05). In study 2, there was a significant difference between control subjects and subjects with cirrhosis for AAMU + 1X + 1U/17U (median for control subjects, 6.2; median for subjects with cirrhosis, 4.3;p= 0.001) but not between control subjects and patients with chronic hepatitis.ConclusionsWe conclude that AAMU + 1X + 1U/17U is affected by liver disease and reflects the decrease in CYP1A2 activity in subjects with cirrhosis. AAMU + 1X + 1U/17U measured from a spot urine sample reflects caffeine clearance in subjects with cirrhosis and may be useful as a hepatic function test. Despite the large interindividual variation observed, the test can be repeated easily in the same patient and an individual patient's decline in CYP1A2 activity, such as in patients with progressively deteriorating liver function, can be monitored.Clinical Pharmacology&Therapeutics(1996)59, 624–635;

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90002-8

年代:1996

数据来源: WILEY

摘要:

Interferon alfa‐2a was chemically modified by the covalent attachment of a polyethylene glycol (PEG) moiety to enhance its circulating half‐life and to reduce its immunogenicity. A comparative evaluation of the pharmacokinetics of the PEG‐modified interferon alfa‐2a showed a greater than twofold increase in the circulating half‐life as a result of this chemical modification. An indirect physiologic response model was developed to characterize the time course of the MX protein response after subcutaneous administration of single ascending doses of either interferon alfa‐2a or PEG‐interferon alfa‐2a in healthy volunteers. Analysis of the pharmacokinetic‐pharmacodynamic relationship suggested that the PEG‐modified interferon alfa‐2a could not be administered less than twice weekly and therefore offered little therapeutic advantage over its unmodified counterpart, which is administered three times weekly. These results were consistent with findings in phase II trials. This study substantiates the usefulness of pharmacodynamic modeling as a tool for the development of dose recommendations and for the early selection of drug candidates in the drug development process.Clinical Pharmacology&Therapeutics(

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90003-X

年代:1996

数据来源: WILEY

摘要:

The pharmacokinetic profile of omeprazole was examined in 27 healthy Japanese volunteers, and the results were analyzed in relation to genotype for the two mutations,CYP2C19m1in exon 5 andCYP2C19m2in exon 4, associated with the poor metabolizer phenotype. Of the 27 individuals analyzed, 10 were homozygous for the wild‐type (wt) allele in both exon 5 and exon 4 (wt/wt; 37.0%, pattern G1), five were heterozygous for theCYP2C19m1(wt/m1; 18.5%, G2), five were heterozygous for theCYP2C19m2(wt/m2; 18.5%, G3), two were heterozygous for the two defects (m1/m2; 7.4%, G4), and five were homozygous for theCYP2C19m1(m1/m1; 18.5%, G5). The allele frequencies of the m1 and m2 mutation were 0.31 and 0.13, respectively. A correlation between the rate of metabolism of omeprazole and genotype was observed. The mean clearance values of omeprazole in patterns G1, G2, G3, G4, and G5 were 1369.0, 332.7, 359.0, 70.8, and 89.5 ml/hr/kg, respectively. The relative area under the serum concentration‐time curve (AUC) ratio of omeprazole to 5‐hydroxyomeprazole in patterns G1, G2, G3, G4, and G5 was 1:2.8:3.4:16:17.2. A similar relation was observed in the omeprazole/5‐hydroxyomeprazole serum concentration ratio, determined 3 hours after drug intake (1:3:4:18.8:20.3). There were significant (p<0.05 to 0.01) differences in the disposition kinetics of omeprazole between the subjects with patterns G1, G2, and G3 and the subjects with patterns G4 and G5. The results indicate that the 5‐hydroxylation pathway of omeprazole is clearly impaired in subjects with m1/m2 and m1/m1.Clinical Pharmacology&Therapeutics(1996)59, 647

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90004-1

年代:1996

数据来源: WILEY

摘要:

ObjectivesTo compare blood concentrations of nicotine and cotinine and maternal and fetal hemodynamic effects resulting from use of nicotine gum versus cigarette smoking in pregnant smokers.MethodsPregnant women (24 to 36 weeks' gestation) who smoked chronically were randomly assigned with a 1:2 randomization scheme to either a group that smoked cigarettes (n= 10) or to a group that stopped smoking and chewed at least six pieces of nicotine gum (2 mg nicotine per piece) per day (n= 19). Blood nicotine and cotinine concentrations, maternal heart rate and blood pressure, uterine resistance index, and fetal heart rate and umbilical artery resistance index were obtained before and after one cigarette was smoked at baseline and after 5 continuous days of either chewing gum or smoking.ResultsA significant reduction from baseline in nicotine (p<0.0001) and cotinine (p<0.0025) concentrations was observed in those who chewed nicotine gum compared with those who smoked cigarettes. No significant differences in the changes in maternal or fetal hemodynamic parameters from baseline to estimated time of peak nicotine exposure were observed between those who smoked cigarettes and those who chewed nicotine gum.ConclusionShort‐term use of nicotine gum delivers less nicotine than usual cigarette smoking in pregnant women.Clinical Pharmacology&Therapeutics(1996)59, 654–661;

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90005-3

年代:1996

数据来源: WILEY

摘要:

F105 is a human monoclonal antibody that binds to the CD4 binding site of human immunodeficiency virus type 1 gp120 and neutralizes clinical and laboratory isolates of the human immunodeficiency virus. This phase I study investigated the disposition of the antibody in humans. F105 was administered over a 60‐minute period at two dose levels, 100 and 500 mg/m2. Blood samples were obtained for up to 56 days. The clearance of the antibody was 0.33 ml/min with a corresponding half‐life of approximately 13 days. Peak concentrations achieved at the higher dose level were 216.19 ± 9.62 μg/ml. The disposition of the drug was linear for the doses studied. Simulations were performed to design future studies aimed at investigating the efficacy of the antibody. This study concluded that F105 can be administered as a bolus dose every 21 days.Clinical Pharmacology&Therapeutics(1996)59, 662–6

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90006-5

年代:1996

数据来源: WILEY

摘要:

BackgroundOne suggested mechanism for the reduction in mortality rates resulting from the use of angiotensin converting enzyme inhibitors in congestive heart failure is the inhibition of the angiotensin II‐mediated norepinephrine release. Direct evidence for this mechanism is lacking in humans.Subjects and MethodsWe examined the effects of captopril, 25 mg three times a day, or matched placebo for 7 days on sympathetic activity during a 10 mEq/day sodium diet in seven healthy male subjects aged 30 ± 3 (SEM) years. A tritiated norepinephrine radioisotope dilution technique was used to measure sympathetic activity, both at rest and during isometric handgrip exercise.ResultsCaptopril blunted the increase in mean arterial pressure during isometric handgrip exercise (placebo, from 81 ± 4 to 112 ± 2 mm Hg; captopril, from 78 ± 3 to 101 ± 2 mm Hg;p<0.01). However, the increase in systemic norepinephrine spillover during isometric handgrip exercise was not blunted by captopril. Captopril had no effect on resting mean arterial pressure or systemic norepinephrine spillover.ConclusionsCaptopril did not attenuate baseline or static exercise‐stimulated sympathetic activity in healthy subjects. These findings would indicate that angiotensin converting enzyme inhibition does not decrease sympathetic activity at rest or during the stimulus of isometric handgrip exercise.Clinical Pharmacology&Therapeutics(1996)59, 668

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90007-7

年代:1996

数据来源: WILEY

摘要:

ObjectivesMazapertine is a structurally novel antipsychotic compound with high affinity for D2, D3, 5‐HT1a, andα1receptors. The objectives were to determine whether tolerance to orthostatic hypotension caused by this compound could be induced by slowly increasing the dose administered and to investigate its effect on cognitive and motor functions.MethodsThirteen healthy male subjects received incremental oral doses of mazapertine (from 5 to 50 mg over 7 days;n= 10) or placebo (n= 3) in part I and single doses in parts II (20 or 30 mg or placebo) and III (40 mg or placebo) in a double‐blind fashion. Blood pressure, heart rate, cardiac hemodynamics, cognitive functions, and occurrence of acute extrapyramidal symptoms were investigated.ResultsMazapertine appears to be safe and well tolerated when administered orally for 7 days to normal healthy men. No accumulation of serum prolactin occurred after multiple dosing, suggesting limited potential for inducing galactorrhea. The drug was rapidly absorbed, and kinetics appeared to be dose dependent, without accumulation. The elimination half‐life was about 5 to 10 hours. No evidence of any positive or negative cognitive effects could be detected. Mild motor symptoms were observed only at high doses (not statistically significant). Mazapertine had a minimal effect on cardiac output and stroke volume. Tolerance to hypotension could be induced by slowly increasing the dose administered.ConclusionsMazapertine is well tolerated when administered orally for seven days, and tolerance to hypotension can be induced by slowly increasing the dose administered. Therefore, nothing precludes further clinical testing on patients with schizophrenia.Clinical Pharmacology&Therapeutics(1996)59, 675–

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90008-9

年代:1996

数据来源: WILEY

摘要:

ObjectiveTo assess the pharmacodynamic activity and safety of rising single and multiple doses of intravenous quinaprilat compared with placebo in patients with New York Heart Association (NYHA) class III and IV congestive heart failure who were receiving digitalis or diuretic therapy or both.MethodsPatients were randomly assigned to three treatment groups to receive low (0.5 and 1.0 mg), medium (1.0 and 2.5 mg), or high (5.0 and 10.0 mg) single intravenous doses of quinaprilat or placebo on day 1. On the basis of responses observed on day 1, the three treatment groups received stable multiple intravenous doses of either quinaprilat or placebo every 6 hours on days 2 and 3. Hemodynamic measurements, hormonal assessments, and safety were evaluated before and at specified intervals during the study.ResultsCompared with placebo, single and multiple doses of quinaprilat increased cardiac index and reduced pulmonary capillary wedge pressure, mean arterial pressure, systemic vascular resistance, and right atrial pressure in a dose‐related manner. No clinically important change in heart rate was observed. Hemodynamic changes after multiple‐dose quinaprilat administration were similar to those observed after single doses and were generally sustained during the 6‐hour dosing interval. Relative to placebo, quinaprilat reduced plasma angiotensin converting enzyme (ACE) activity, angiotensin II concentration, and aldosterone concentration and increased plasma renin activity; no prominent changes in plasma catecholamine and atrial natriuretic peptide concentrations were observed. There were no clinically important drug‐related changes in the safety parameters.ConclusionsSingle and multiple intravenous doses of 0.5 to 10 mg quinaprilat are well‐tolerated and produce favorable dose‐dependent hemodynamic effects and hormonal changes consistent with those expected of an ACE inhibitor in patients with NYHA class III and IV congestive heart failure.Clinical Pharmacology&Therapeutics(1996)59, 6

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90009-0

年代:1996

数据来源: WILEY