摘要:

Clinical Pharmacology&Therapeutics(1996)60, 363–367; do

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90192-7

年代:1996

数据来源: WILEY

摘要:

Clinical Pharmacology&Therapeutics(1996)60, 368–373; do

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90193-9

年代:1996

数据来源: WILEY

摘要:

Dextromethorphan is used widely in vivo to phenotype the polymorphically expressed cytochrome P450 (CYP) 2D6. Dextromethorphan isN‐demethylated in vitro to 3‐methoxymorphinan by human CYP3A4/5. We examined whether the dextromethorphan/3‐methoxymorphinan urinary metabolic ratio (MR) could be used as an in vivo probe of CYP3A. Urinary excretion of 3‐methoxymorphinan was excretion rate‐limited in extensive metabolizers of CYP2D6, which necessitated a longer urine collection, 0 to 72 hours, to obtain true MR values for CYP3A. The urine excretion of dextromethorphan and 3‐methoxymorphinan was delayed in poor metabolizers of CYP2D6 but appeared to be formation rate‐limited. The delayed excretion in poor metabolizers necessitated longer urine collection intervals, 0 to 11 days, to estimate the true CYP3A MR and 0 to 8 days to estimate the true CYP2D6 MR. However, a 72‐hour collection in poor metabolizers was used as an index of the true dextromethorphan/3‐methoxymorphinan MR. Rifampin (300 mg b.i.d. for 7 days) significantly reduced the 0‐ to 72‐hour dextromethorphan/3‐methoxymorphinan MR consistent with an 830% (±1808%) induction of CYP3A activity (n= 8), whereas erythromycin (250 mg q.i.d. for 7 days) significantly increased the dextromethorphan/3‐methoxymorphinan MR, corresponding to a 34% ± 44% inhibition of activity (n= 7) in extensive metabolizers and poor metabolizers. The changes in CYP3A activity were independent of CYP2D6 phenotype and were also observed after 24‐ and 48‐hour urine collections in extensive metabolizers and poor metabolizers. In addition, MRs reflecting CYP2D6 and CYP3A were not significantly correlated. We conclude that the commonly used antitussive dextromethorphan can be used as an in vivo marker of CYP3A and CYP2D6 activity.Clinical Pharmacology&The

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90194-0

年代:1996

数据来源: WILEY

摘要:

RationaleFor high‐clearance drugs such as nicotine, hemodynamic changes throughout the day may be expected to influence the rate of metabolism.Material and methodsTo assess the effects of meals and diurnal rhythms on nicotine clearance, an intravenous infusion of nicotine bitartrate was administered for 48 hours to 11 subjects. Two models to determine nicotine clearance variation throughout the day are described. Both models were used to estimate the mean effect of meal and diurnal rhythms on nicotine clearance and individual parameters that were regressed against baseline covariates. Clearance was modeled as a function of time [CL(t)] and split it in three components: a (constant) baseline value (θ1, its circadian (diurna) variation, and the effect of meal: CL(t) = [θ1+ circadian(t)] [1 + meal(t)]. A two‐compartmental (time‐variant) model incorporating CL(t) was then fitted to the data providing estimates of CL(t) conditional on literature values of the time‐invariant parameters (volume of distribution and intercompartmental clearances).ResultsThe estimated circadian(t) showed a maximum at approximately 11AMand a flat minimum from 6PMto 3AM; the estimated meal(t) showed a sharp increase up to 1 hour (after the meal), at which point clearance is increased 42%, and a slower decrease thereafter, returning to baseline (zero) after 2.8 hours. Individual estimates of baseline clearance are found to have a linear relationship with body weight. No other covariate, sex in particular, effect could

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90195-2

年代:1996

数据来源: WILEY

摘要:

ObjectivesTo determine the effects of omeprazole on indexes of CYP2D6, CYP2C19 and 3A in vivo activity and to compare these in white subjects and Chinese subjects.MethodsOmeprazole, 40 mg/day, or placebo were administered in a double‐blind crossover study for 3 weeks to eight healthy white and seven Chinese male extensive metabolizers of mephenytoin and debrisoquin. Debrisoquin (10 mg), dapsone (100 mg), and mephenytoin (100 mg) were given 1 week before administration, on the last day of administration, and 3 weeks after administration, and urine was collected over 8 hours. Phenotypic trait values were obtained from the urinary recoveries of the probe drugs or their metabolites.ResultsIn the white subjects, omeprazole significantly inhibited CYP2C19‐mediatedS‐mephenytoin metabolism as indicated by decreases in the urinary R/S enantiomeric ratio (63% ± 13%;p<0.02; mean ± SD) and the excretion of 4′‐hydroxymephenytoin (39% ± 13%;p<0.001). Similar but smaller changes were also noted in Chinese subjects, 22% ± 25% (p= 0.08) and 29% ± 13% (p<0.002), respectively. The interracial differences in the extent of inhibition of metabolism were statistically significant (p<0.01 andp<0.05, respectively). In contrast, the debrisoquin urinary metabolic ratio, a measure of CYP2D6, was unaffected. The excretion of hydroxylamine dapsone—a putative probe of CYP3A activity—was reduced by 40% ± 30% (p<0.03) in white subjects but not in Chinese subjects.ConclusionsOmeprazole selectively inhibits the in vivo metabolism ofS‐mephenytoin, consistent with the predictions based on in vitro studies. The extent of interaction is greater in subjects of white European ancestry. It is to be expected that similar situations would also occur when omeprazole is coadministered with other substrates of CYP2C19.Clinical Pharmacology&Therapeutics(

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90196-4

年代:1996

数据来源: WILEY

摘要:

ObjectiveDefine the pharmacokinetics of bumetanide after single intravenous doses in volume‐overloaded critically ill infants.MethodsA prospective, open‐label study was carried out in a group of 58 infants aged 0 to 6 months who required diuretic therapy. Each patient received a single dose of intravenous bumetanide. Doses selected in sequential order ranged from 0.005 to 0.10 mg/kg. Hematologic and serum chemistry studies were performed before and at 6 and 24 hours after bumetanide administration. Determinations of urine volume and chemistries were performed before (collected from −2 to −4 hours to time 0) and at 1, 2, 3, 4, 6, and 12 hours after bumetanide dosing. Serum samples collected at time 0 and at 5, 15, 30, 60, 120, 180, 240, 360, and 480 minutes and urine collected at time 0 and at 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, and 6 to 12 hours were analyzed for bumetanide concentration. Data were evaluated by standard noncompartmental pharmacokinetic techniques.ResultsPeak serum bumetanide concentrations occurred at 5 minutes after bumetanide administration. Area under the curve and peak serum bumetanide concentrations showed linear increases over the twentyfold dose range; whereas beta volume of distribution, volume of distribution at steady state, clearance, renal clearance, half‐life, and mean residence time values were independent of dose. Peak urinary excretion rates of bumetanide increased linearly with increasing doses. The mean percent of bumetanide recovered in the urine from 0 to 12 hours was 40% ± 15% of the administered dose.ConclusionsDistribution and elimination kinetics of bumetanide were similar in all patients. Elimination kinetics were first order over the dose range of 0.005 to 0.10 mg/kg. Pharmacokinetic parameter estimates (beta volume of distribution, volume of distribution at steady state, clearance, renal clearance, half‐life, and mean residence time) were independent of the dose of bumetanide administered. Single doses of bumetanide up to 0.10 mg/kg appear to be well tolerated in acutely ill volume‐overloaded infants aged 0 to 6 months.Clinical Pharmacology&Therapeutics(1996)60

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90197-6

年代:1996

数据来源: WILEY

摘要:

ObjectivesAccount for the interindividual variability in the pharmacokinetics and pharmacodynamics of bumetanide after intravenous administration of single doses to critically ill infants.MethodsThis prospective open‐label study was carried out in the pediatric intensive care unit of a university‐based children's hospital. Fifty‐three volume‐overloaded critically ill infants (age range, 4 days to 6 months) were divided into two groups: those with heart disease (31 infants) and those with lung disease (22 infants). Each patient received a single intravenous bolus dose of bumetanide. Doses, selected in sequential order, ranged from 0.005 to 0.100 mg/kg. Age was used as a continuous variable to determine its effects on the variability in the pharmacokinetics and pharmacodynamics of bumetanide. Hierarchical multiple regression analyses were used to assess the effects of age, disease, and other drugs on the variability in the effects of bumetanide.ResultsTotal clearance, renal clearance, and nonrenal clearance of bumetanide all increased with age (p<0.05), but the ratio of renal clearance to total clearance remained constant at about 0.4. Half‐life and mean residence time decreased markedly in the first month of life (p<0.05). Bumetanide excretion rate normalized for dose also increased with increasing age. Patients with lung disease exhibited a significantly greater clearance and shorter half‐life (p<0.05) than those with heart disease, whereas volume of distribution was similar in both groups. The primary determinant of bumetanide excretion rate was the administered dose (73%). Dose‐response curves for urine flow rate and electrolyte excretion were similar between disease groups. The time course of the effect of bumetanide excretion rate on pharmacodynamics responses was similar between disease groups, as was the duration of the diuretic effect.ConclusionsThe pharmacokinetics of bumetanide were influenced significantly by age and disease. Differences in pharmacokinetics between patients with lung and heart disease were primarily due to differences in total clearance. The administered dose of bumetanide and age were positive determinants of bumetanide excretion rate and pharmacodynamic responses. Pharmacodynamic responses as a function of bumetanide excretion rate were not significantly different between disease groups.Clinical Pharmacology&Therapeutics(1996)60,

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90198-8

年代:1996

数据来源: WILEY

摘要:

ObjectivesDetermine the diuretic effects of single intravenous doses of bumetanide in volume‐overloaded critically ill infants.MethodsA prospective, open‐label study was carried out in 56 infants aged 0 to 6 months who required diuretic therapy. Each patient received a single intravenous dose of bumetanide. Doses selected in sequential order ranged from 0.005 to 0.10 mg/kg. Determinations of urine volume, electrolytes, creatinine levels, and osmolality were performed before (collected from −2 to −4 hours to time 0) and at 1, 2, 3, 4, 6, and 12 hours after bumetanide dosing. Serum samples collected at time 0 and at 5, 15, 30, 60, 120, 180, 240, 360, and 480 minutes and urine aliquots collected at time 0, 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, and 6 to 12 hours were analyzed for bumetanide concentration. Individual changes in urine flow rate and electrolyte excretion were plotted against corresponding bumetanide excretion rates, taken as the effective dose of the drug.ResultsPeak bumetanide excretion rates increased linearly with increasing doses of drug. Time course patterns for urine flow rate and electrolyte excretion were similar for all dosage groups. Urine flow rate and electrolyte excretion increased linearly up to a bumetanide excretion rate of approximately 7 μg/kg/hr and either plateaued (urine flow rate) or declined at a bumetanide excretion rate of>10 μg/kg/hr. Diuretic efficiency of bumetanide was maximal at doses of 0.005 to 0.010 mg/kg but decreased at higher doses.ConclusionsMaximal diuretic responses occurred at a bumetanide excretion rate of about 7 μg/kg/hr, corresponding to doses of 0.035 to 0.040 mg/kg. Higher doses produced a proportionately higher bumetanide excretion rate but no increased diuretic effect. Lower doses of bumetanide had the greatest diuretic efficiency, suggesting that continuous infusion of low doses of bumetanide or intermittent low‐dose boluses may produce optimal diuretic responses in critically ill infants.Clinical Pharmacology&Therapeutics(1996)60,

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90199-X

年代:1996

数据来源: WILEY

摘要:

ObjectivesTo study potency, efficacy, development of tolerance, and mechanism of action of substance P, an endothelium‐dependent vasodilator neurokinin, in human hand veins in vivo.MethodsThirty‐three healthy subjects were studied with use of the hand vein compliance technique. In hand veins preconstricted with theα1‐agonist phenylephrine, substance P and antagonists of nitric oxide formation (L‐NG‐mono‐methyl‐arginine,L‐NMMA), adenosine triphosphate (ATP)‐dependent potassium channels (glyburide), angiotensin converting enzyme (enalaprilat), and cyclooxygenase (acetylsalicylic acid) were infused and the venodilator effect was measured.ResultsSubstance P proved to be the most potent venodilator known thus far (the dose‐rate exerting 50% of mean maximum dilation [ED50], geometric mean: 0.105 pmol/min). Rapid development of tolerance occurred in seven of eight volunteers studied. Glyburide decreased the venodilator action of a single dose of substance P (1.5 pmol/min) from 81% to 28% of baseline venodilation (p<0.05), suggesting that substance P acts through release of endothelium‐derived hyperpolarizing factor. The cyclooxygenase‐inhibitor acetylsalicylic acid reduced substance P‐induced venodilation from 53% ± 7% to 34% ± 8% (p<0.05), whereasL‐NMMA had no effect.ConclusionsUnlike in other vessels, substance P‐induced venodilation in hand veins is not mediated through nitric oxide but to a significant extent through a glyburide‐sensitive pathway. Therefore it appears likely that substance P activates ATP‐dependent potassium channels on vascular smooth muscle cells through the release of endothelium‐derived hyperpolarizing factor.Clinical Pharmacol

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90200-3

年代:1996

数据来源: WILEY

摘要:

BackgroundRecent studies have shown that insulin has a direct vasodilator effect and that vascular sensitivity to insulin is impaired in hypertension. How the vasodilator effect of insulin is regulated physiologically is unknown. It has been appreciated that salt restriction may have adverse effects on glucose and lipid metabolism—processes regulated by insulin. To determine whether dietary salt restriction might affect vascular sensitivity to insulin, we studied 13 subjects (including eight borderline hypertensive subjects and five normotensive subjects) after 1 week of a normal sodium diet (240 mEq/day) and after 1 week of a low‐sodium diet (20 mEq/day) with a randomized, double‐blind crossover design.Methods and ResultsVascular sensitivity to insulin was assessed with the dorsal hand vein linear variable differential transformer technique. When the “normal” salt diet was given, vascular sensitivity for insulin was significantly less (i.e., dose that produced the half‐maximal response [ED50] insulin was higher) in hypertensive subjects (ED50insulin for hypertensive subjects, 5.75 milliunits (mU)/min; ED50insulin for normotensive subjects, 0.23 mU/min;p<0.05). Vascular sensitivity to insulin was inversely correlated with mean arterial pressure and plasma norepinephrine concentration. When the low salt diet was given, vascular sensitivity to insulin decreased in both the normotensive and hypertensive groups, paralleling an increase in plasma norepinephrine. Blood pressure was not significantly decreased by reducing salt intake.ConclusionIn these younger normotensive and hypertensive subjects, dietary salt restriction increases resistance to the vasodilating effects of insulin.Clinical Pharmacology&Therapeutics(1996)60, 4

ISSN:0009-9236    

DOI:10.1016/S0009-9236(96)90201-5

年代:1996

数据来源: WILEY