摘要:

Clinical Pharmacology and Therapeutics(1991)49,481–487; doi:10.1038/clpt.1991.

ISSN:0009-9236    

DOI:10.1038/clpt.1991.58

年代:1991

数据来源: WILEY

摘要:

Encainide metabolism is mediated by the polymorphically distributed cytochrome P450IID6, which displays stereoselectivity for some substrates. In this study we found that urinary recovery during steady‐state encainide in three poor metabolizers was high (49% to 80%), consisted mainly of unchanged encainide, was nonstereoselective (± ratio, 0.985 to 1.049), and was unchanged by quinidine, a potent inhibitor of P450IID6. In contrast, in seven extensive metabolizers the ± urinary ratios were 1.20 ± 0.06 for encainide and 0.81 ± 0.06 (bothp<0.01) for the cytochrome P450IID6 productsO‐desmethylencainide plus 3‐methoxy‐O‐desmethylencainide; with quinidine the total percentage recovery rose from 4% ± 4% to 37% ± 9% because of increased recovery of unchanged encainide and became nonstereoselective (± ratio, 0.84 ± 0.08 [encainide alone] versus 0.97 ± 0.05 [encainide plus quinidine]). In vitro, encainide enantiomers depressed the maximum rate of metabolism with similar frequency and concentration dependence. We conclude that (‐)‐encainide undergoes preferential metabolism by cytochrome P450IID6; however, this genetically determined stereoselective disposition is unlikely to play a major role in mediating the clinical actions of encainide.Clinical Pharmacology and Therapeutics(1991)49,488–496;

ISSN:0009-9236    

DOI:10.1038/clpt.1991.59

年代:1991

数据来源: WILEY

摘要:

Kinetic modeling has been applied to the time course of the nuclear magnetic resonance signal intensities of 5‐fluorouracil and the sum of its catabolites, α‐fluoro‐β‐ureido propanoic acid and α‐fluoro‐β‐alanine, as monitored in liver tumors of seven patients with cancer after brief intraarterial infusion of 5‐fluorouracil. Because these data represent only relative tissue concentrations, only ratios of clearance and volume parameters can be estimated (e.g., clearance/central volume of distribution or central volume of distribution/steady‐state volume of distribution). On the other hand, parameters that do not refer to volumes, such as half‐lives or maximal velocity of metabolic conversion of a nonlinear model, can be estimated in absolute terms. A nonlinear three‐compartment model gave satisfactory fits with all of the individual data sets. Kinetics of 5‐fluorouracil and catabolites were similar in five patients with metastases of colorectal adenocarcinomas but differed from those of two patients with cholangiocarcinoma and metastases of an anaplastic carcinoma of unknown origin, respectively.Clinical Pharmacology and Therapeutics(1991)49,497

ISSN:0009-9236    

DOI:10.1038/clpt.1991.60

年代:1991

数据来源: WILEY

摘要:

There are no safe and effective oral drugs to treat leishmaniasis and Chagas' disease. The safety, pharmacokinetics, and metabolism of single and multiple oral doses of allopurinol riboside, an investigational antiparasitic agent, were evaluated in a randomized, double‐blinded, placebo‐controlled study in 32 healthy male volunteers, at levels up to 25 mg/kg q.i.d. for 13 doses. No significant toxicity was detected. Allopurinol riboside peaks in plasma 1.6 hours after administration, has an elimination half‐life of 3 hours, and steady‐state concentrations in the therapeutic range. However, in contrast to preclinical studies in dogs (plasma levels proportional to oral doses up to 200 mg/kg), we found that plasma levels were unexpectedly low and did not rise with increasing dose. Furthermore, allopurinol and oxypurinol (unanticipated metabolites) were detected at levels proportional to the dose of allopurinol riboside. We present a model that includes incomplete absorption, metabolism of residual drug by enteric flora, and absorption of bacterial metabolites to explain these findings in humans.Clinical Pharmacology and Therapeutics(1991)49,506–514; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1991.61

年代:1991

数据来源: WILEY

摘要:

To determine the influence of sampling site on atracurium pharmacokinetic‐pharmacodynamic relationships, blood was drawn simultaneously from the radial artery and a peripheral vein during a 20‐minute period after injection of atracurium, 0.2 mg/kg, in eight patients. Atracurium and laúdanosme concentrations were measured by HPLC. Neuromuscular blockade was measured at the adductor pollicis, after stimulation of the ulnar nerve. Venous levels were lower than corresponding arterial values for up to 20 minutes, and this difference was marked for the early samples. Neuromuscular blockade was maximum after 5 to 7 minutes, much later than the peak venous concentration (1 to 3 minutes). Nonparametric analysis yielded (mean ± SEM) a rate constant, concentration for 50% blockade, and slope of the effect‐concentration relationship of 0.092 ±0.01 min−1, 379 ± 27 ng/ml, and 7.3 ± 1.67, respectively, when based on arterial samples. The values were statistically different (0.135 ± 0.011 min−1, 235 ± 42 ng/ml, and 3.41 ± 0.37, respectively) when venous levels were used(p<0.05). It is concluded that forearm venous levels do not correspond to adductor pollicis neuromuscular blockade and the kinetics and kinetic‐dynamic relationship for atracurium are heavily dependent on sampling site.Clinical Pharmacology and Therapeutics(1991)49,515–522; do

ISSN:0009-9236    

DOI:10.1038/clpt.1991.62

年代:1991

数据来源: WILEY

摘要:

The pharmacokinetics of didanosine (2',3'‐dideoxyinosine) after intravenous and oral administration were evaluated in an open, escalating‐dose phase I study in patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS‐related complex. Didanosine was administered twice a day for 2 weeks as an intravenous infusion of 60 minutes duration at doses ranging from 0.4 to 16.5 mg/kg, followed by 4 weeks of oral treatment at twice the intravenous dose. Serial blood and urine samples were obtained on the first and final day of intravenous administration and after the first oral dose, as well as at steady state. Didanosine demonstrated linear pharmacokinetic behavior over the dose ranges of 0.4 to 16.5 mg/kg intravenously and 0.8 to 10.2 mg/kg orally. There was no indication of significant changes in pharmacokinetic parameters with repeated administration. The apparent elimination half‐life after oral administration was approximately 1.4 hour. Renal clearance values exceeded the glomerular filtration rate, indicating that active tubular secretion of didanosine occurs. Bioavailability of didanosine when administered as a solution with an antacid was approximately 43% for doses from 0.8 to 10.2 mg/kg in patients with AIDS and advanced AIDS‐related complex. Bioavailability of didanosine from the citrate‐phosphate‐buffered solution, the formulation currently used in phase II and expanded access studies, was comparable to the formulation used in the phase I trials.Clinical Pharmacology and Therapeutics(1991)49,523–535; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1991.63

年代:1991

数据来源: WILEY

摘要:

Methylprednisolone pharmacokinetics and its directly suppressive effects on plasma cortisol, blood histamine (basophils), and circulating helper T cells were evaluated in six obese (at least 35% above ideal body weight) men and six nonobese male volunteers. Methylprednisolone doses of 0.6 mg/kg total body weight were administered as the 21‐succinate sodium salt. Absolute clearance (in liters per hour) of methylprednisolone was 40% less in the obese subjects. Total volume of distribution (Vss) of methylprednisolone was unchanged (about 120 L), but when normalized for total body weight, Vssper kilogram was less in obesity. The patterns of cortisol, blood histamine, and helper T cell responses after methylprednisolone administration were similar in both groups, but more profound effects were observed in the obese subjects. Pharmacodynamic models were applied for these immediate effects of methylprednisolone based on the premise that receptor interactions of steroids are followed by rapid suppression of the circadian rhythm of cortisol and recirculation of basophils and helper T cells, which persist until inhibitory concentrations (IC50) of methylprednisolone disappear. Similar IC50values for the three effects were obtained in both groups, indicating no intrinsic pharmacodynamic differences in sensitivity to these methylprednisolone effects in obesity. However, methylprednisolone should be administered on the basis of ideal body weight, and the dosing interval should be potentially lengthened because of decreased methylprednisolone clearance in obesity.Clinical Pharmacology and Therapeutics(1991)49,536–549; doi:10.1038/clpt.199

ISSN:0009-9236    

DOI:10.1038/clpt.1991.64

年代:1991

数据来源: WILEY

摘要:

The population pharmacokinetics of intravenous indomethacin were investigated with 665 indomethacin serum concentrations from 83 neonates (mean ± SD: gestational age, 28.8 ± 2.5 weeks; postnatal age, 5.7 ± 4.7 days; birth weight, 1.13 ± 0.40 kg) receiving indomethacin for symptomatic patent ductus arteriosus. A one‐compartment open model was used for pharmacokinetic analysis. Hypotheses were tested to determine which developmental and demographic data influenced clearance (CL) and volume of distribution (Varea). In the final regression equation CL and Vareawere modeled as a function of body weight and postnatal age (PNA) from 0 to 20 days. Final estimates were as follows: CL (ml/hr) = 2.63 · weight (kg) + 0.244 · PNA (days) and Varea(L) = 0.28 · weight (kg) + 0.0041 · PNA (days). The coefficients of variation for interindividual variability in CL and Vareawere 77% and 28%, respectively. Intraindividual variability was 19%. These mean population parameter estimates should prove useful in designing dosage regimens to achieve desired indomethacin concentrations for neonates from 0 to 20 days of age with symptomatic patent ductus arteriosus.Clinical Pharmacology and Therapeutics(1991)49,550–557; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1991.65

年代:1991

数据来源: WILEY

摘要:

The effects of ketoconazole on the pharmacokinetics and pharmacodynamics of intravenous prednisolone (14.8 mg) were assessed in six healthy volunteers. Subjects were studied with and without receiving ketoconazole, 200 mg orally for 6 days. The addition of ketoconazole did not significantly change the clearance (96 ±11 versus 90 ± 11 ml/hr/kg), mean residence time (4.29 ± 0.43 versus 4.45 ± 0.59 hours), volume of distribution (0.41 ± 0.02 versus 0.40 ± 0.02 L/kg), or plasma protein binding characteristics of prednisolone. The suppressive effects of prednisolone on serum cortisol, blood ba‐sophil, and helper T lymphocyte values, assessed by the ratio of the area under the curve (AUC) after prednisolone administration to the baseline AUC, was not altered significantly by ketoconazole. The 50% inhibitory concentration values derived from pharmacodynamic models developed to describe the direct suppressive effects of corticosteroids indicated no alteration in intrinsic sensitivity in the presence of ketoconazole. Ketoconazole does not appear to alter the pharmacokinetics or the pharmacodynamic response patterns of selected direct suppression effects of single low doses of prednisolone.Clinical Pharmacology and Therapeutics(1991)49,558–570; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1991.66

年代:1991

数据来源: WILEY

摘要:

The influence of mexiletine (200 mg every 8 hours) on theophylline metabolism was studied in young male(n= 7) and female(n= 8) nonsmokers. A single‐dose study of theophylline kinetics was performed at baseline and after 5 days of mexiletine treatment. With mexiletine the plasma clearance of theophylline decreased from 33.5 ± 2.6 (mean ± SEM) to 17.9 ± 1.0 ml/kg per hour in the female group(p<0.001) and from 32.3 ± 2.6 to 19.3 ± 1.3 ml/kg per hour in the male group(p<0.001). The elimination half‐life was prolonged by 74% and 103% in the male and female groups, respectively. Mexiletine decreased the formation of all theophylline metabolites in both groups. Within each group, the demethylation pathways were affected more than the hydroxylation pathway. These data indicate that mexiletine is a potent inhibitor of theophylline metabolism. This effect is not influenced by gender. Concurrent administration of these drugs may require a dose reduction of theophylline by as much as 50% to minimize the risk of toxicity.Clinical Pharmacology and Therapeutics(1991)49,571–580; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1991.67

年代:1991

数据来源: WILEY