摘要:

Presystemic inversion of(R)‐to(S)‐ibuprofen has been proposed but not directly examined in humans. We investigated the bioavailability of the enantiomers of ibuprofen in 10 healthy volunteers. Low‐dose racemic ibuprofen (400 mg) was administered orally and intravenously (60‐minute infusion), in random order. There were no significant differences between oral and intravenous doses for the area under the curve values, terminal rate constants, clearances, metabolite formation clearances, and serum protein binding for(R)‐and(S)‐ibuprofen. The bioavailabilities of(R)‐ibuprofen and total ibuprofen were 0.92 ± 0.11 and 0.95±0.08, respectively. The fractional inversion of(R)‐ibuprofen was determined by two methods (stable isotope method and from the stereochemical composition of the urinary metabolites) that gave similar estimates of inversion for oral dosing (0.56 ± 0.12 and 0.60 ± 0.07, respectively) and intravenous dosing (0.56 ± 0.09 and 0.60 ± 0.06, respectively). We conclude that the bioavailability of both enantiomers of ibuprofen is complete and find no evidence of significant presystemic inversion.Clinical Pharmacology and Therapeutics(1993)53,393–400;

ISSN:0009-9236    

DOI:10.1038/clpt.1993.42

年代:1993

数据来源: WILEY

摘要:

Potent inhibition of cytochrome P450 2D6 (CYP2D6) in human liver microsomes by fluoxetine and its major metabolite norfluoxetine was confirmed (apparent inhibition constant values, 0.2 μmol/L). Several other serotonergic agents were also found to be competitive inhibitors of this genetically polymorphic enzyme. TheO‐demethylation ratio of dextromethorphan that expressed CYP2D6 activity in 19 patients receiving fluoxetine fell in the region of the antimode separating theO‐demethylation ratio values observed in 208 extensive metabolizers from 15 poor metabolizers of a control group of healthy subjects. Inhibition of CYP2D6 activity in patients undergoing treatment with fluoxetine or other serotonin uptake inhibitors could contribute to toxicity or attenuated response from concurrent medications that are substrates of this enzyme. Other in vitro studies indicated that CYP2D6 catalyzes theO‐demethylation of oxycodone to form oxymorphone. This reaction was inhibited by fluoxetine and its normetabolite in liver microsomes from both extensive and poor metabolizer individuals, indicating that these compounds are not selective inhibitors of CYP2D6 activity.Clinical Pharmacology and Therapeutics(1993)53,401–409; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1993.43

年代:1993

数据来源: WILEY

摘要:

Debrisoquin hydroxylation phenotype was determined in 124 Chinese persons living in Taiwan, and two poor metabolizers were identified with a urinary metabolic ratio (MR) greater than 12.6. The other subjects, extensive metabolizers, showed a normal frequency distribution of log(MR). Most subjects (50%) showed a 44/29 kb pattern in restriction fragment length polymorphism (RFLP) analysis with use ofXbaI, and 30% and 15% of the subjects exhibited a homozygous 29/29 kb and 44/44 kb pattern, respectively. Among extensive metabolizers, subjects with the 44/44 kb pattern had a significant higher log(MR) than those with the 44/29 pattern, and the log(MR) of the subjects with the 44/29 kb pattern was significantly higher than that of the subjects with 29/29 kb pattern. All nine exons and intron 3 ofCYP2D6were amplified with polymerase chain reaction (PCR) and sequenced for four extensive metabolizers. Two major polymorphisms were found: one at position 188 of exon 1 and the other at position 4268 in exon 9. With PCR and endonuclease digestion, polymorphisms at exon 1, intron 3, and exon 9 were investigated. Only two of 254 alleles showed a heterozygous guanine at 1934 base pairs (G1934) to adenine (A) mutation, commonly found in white poor metabolizers. Approximately 70% of alleles showed thymine at 188 base pairs (T188), and 76% showed cytosine at 4268 base pairs (C4268) instead of C188and G4268, as is found in most white subjects. Subjects with T188or C4268 showed a significant higher log(MR) than subjects with homozygous C188and G4268. The C/T188, G/A1934, G/C4268, and RFLP polymorphisms may explain the interracial variations between Chinese and white subjects, as well as the genetic variations among Chinese subjects.Clinical Pharmacology and Therapeutics(1993)53,410–418; doi:10.1038/clpt.1993.

ISSN:0009-9236    

DOI:10.1038/clpt.1993.44

年代:1993

数据来源: WILEY

摘要:

To elucidate the physiologic basis of multicompartmental systems used to model drug distribution, we studied inulin and15N2‐urea kinetics after simultaneous intravenous injection in five normal subjects. Distribution of both compounds was characterized by three‐compartment models in which the central compartment corresponded to intravascular space. The mean distribution volumes of 0.164 ± 0.009 L/kg (± SD) for inulin and of 0.670 ± 0.143 L/kg for urea were similar to expected values for extracellular space and total body water, respectively. Distribution from intravascular space was kinetically heterogeneous, presumably reflecting differences in vascular beds supplied by either fenestrated and discontinuous capillaries or capillaries with a continuous basement membrane. Intercompartmental clearances of inulin and urea and the ratio of their free water diffusion coefficients were used to estimate blood flows and permeability coefficient‐surface area products for the peripheral compartments. The sum of compartmental blood flows averaged 5.39 ± 0.49 L/min and was similar to dual‐beam Doppler measurements of cardiac output (5.47 ± 0.40 L/min).Clinical Pharmacology and Therapeutics(1993)53,419–425; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1993.45

年代:1993

数据来源: WILEY

摘要:

We measured ivermectin in plasma, urine, and saliva of nine patients with onchocerciasis. The aim was to establish pharmacokinetic parameters and to assess the most facile medium for use in monitoring compliance. Binding of ivermectin to plasma proteins in vitro was also investigated. The mean (± SEM) plasma values for the nine subjects were as follows: weight, 66.3 ± 2.8 kg; dose, 11.11 ± 0.4 mg; half‐life, 56.50 ± 7.01 hours; clearance, 142.5 ± 22.6 L/kg; volume of distribution, 9.91 ± 2.67 L/kg; area under the plasma concentration—time curve, 1545.3 ± 190.5 ng/ml · hr; time to reach maximum concentration, 4.7 ± 0.5 hours; and maximum concentration, 38.2 ± 5.8 ng/ml. Ivermectin was not detected in the urine of any of the nine subjects. Low levels were found in saliva. Blood specimens remain the only reliable biologic fluid for assessment of compliance after ivermectin oral administration. Ivermectin binds specifically to human serum albumin.Clinical Pharmacology and Therapeutics(1993)53,426–430; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1993.46

年代:1993

数据来源: WILEY

摘要:

The pharmacokinetics of the second‐generation H1‐receptor antagonist cetirizine was studied in eight children younger than 4 years of age who were treated with a single dose of cetirizine solution (5 mg). These children were hospitalized with suspected allergic respiratory problems or recurrent respiratory tract infections. Blood samples were collected at ½, 1, 1½, 2, 4, 6, 8, 12, and 24 hours, and a 24‐hour urine collection was performed in five of the samples. The findings obtained in children were compared with those obtained in 16 healthy young adults (mean ± SD, 24.6 ±4.1 years) who received a single 20 mg dose. Cetirizine was absorbed more slowly in children(p= 0.006; mean ± SD, 1.44 ± 1.12 hours) than in adults (0.62 ± 0.22 hours). The plasma elimination half‐life of cetirizine was significantly shorter in children(p<0.001; 4.91 ± 0.6 hours) than in adults (8.6 ± 2.1 hours), and the clearance rate was significantly higher in children(p<0.001; 1.48 ± 0.41 ml/min/kg) than in adults (0.80 ± 0.17 ml/min/kg). Urinary excretion of unchanged cetirizine was significantly lower in children(p<0.001; 37.8% ± 5.2%;n= 5) than in adults (57.7% ± 11.8%). Therefore the metabolism of cetirizine is faster in young children than in adults. This effect must be taken into account in future pharmacodynamic studies in this age group.Clinical Pharmacology and Therapeutics(1993)53,431–435; d

ISSN:0009-9236    

DOI:10.1038/clpt.1993.47

年代:1993

数据来源: WILEY

摘要:

d‐Sotalol was developed as an antiarrhythmic agent with a relative lack of antagonist activity at β‐adrenergic receptors. Exercise heart rate reduction has been observed after administration to humans. The purpose of this study was to determine directly whether this effect ofd‐sotalol was attributable to β ‐blockade. Plasma samples from normal volunteers who randomly received either atenolol,d‐sotalol, or placebo were used in an in vitro radioreceptor assay to determine occupancy of β‐adrenergic receptors by antagonist present in the plasma. Occupancy was compared with the observed pharmacologie effects. A reduction in exercise heart rate of 7.7% ± 3.8% ford‐sotalol and 15.9% ± 3.0% for atenolol occurred with β1‐adrenergic receptor occupancy of 0% and 33.9% ± 21.4%, respectively. Absence of antagonist effect in the radioreceptor assay eliminates the potential role of β1‐blockade ind‐sotalol— induced heart rate reduction. This effect is most likely a result of prolongation of the sinus node action potential duration.Clinical Pharmacology and Therapeutics(1993)53,436

ISSN:0009-9236    

DOI:10.1038/clpt.1993.48

年代:1993

数据来源: WILEY

摘要:

The effects of single intravenous doses of 0.25, 0.50, and 0.75 mg/kg moxisylyte on maximum urethral closure pressure were evaluated in a placebo‐controlled double‐blind experiment in 20 patients with spinal cord injuries. Pharmacodynamic testing was performed until 30 minutes, and blood pressure was assessed until 60 minutes. Our findings showed a dose‐dependent decrease in maximum urethral closure pressure. At each individual time point, the three doses differed significantly from placebo. Ten minutes after dose administration the maximum effect (48% decrease) was obtained with 0.75 mg/kg. A significant difference in favor of the highest dose was shown from 15 to 20 minutes after administration. According to these findings and because 0.75 mg/kg was as well tolerated as the two other doses, such a drop in pressure indicates that the α‐blocking agent moxisylyte may be an effective means of decreasing urethral resistance, with obvious implications for the management of urinary obstruction.Clinical Pharmacology and Therapeutics(1993)53,443–449; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1993.49

年代:1993

数据来源: WILEY

摘要:

Although studies indicate that converting enzyme inhibitors such as captopril influence α‐adrenergic physiology, the data on α‐adrenergic physiology is inconsistent. This study therefore examined the effects of captopril (50 mg/day for 5 days) during sodium restriction on the pressor response and on angiotensin II and neuropeptide Y levels to infused norepinephrine (0.01 to 0.1 μg/kg/min) in 17 hypertensive and 27 normotensive subjects. Angiotensin II increased significantly in response to infused norepinephrine during placebo administration(p<0.001) but not during captopril administration(p= 0.15). Neuropeptide Y levels decreased in response to captopril(p= 0.02). Despite these changes the pressor response to infused norepinephrine was unchanged with captopril. These data support the conclusion that the antihypertensive action of captopril is unrelated to alterations in norepinephrine‐mediated α‐adrenergic pressor regulation. The finding of a decrease in neuropeptide Y levels may have relevance to the therapeutic effects of captopril.Clinical Pharmacology and Therapeutics(1993)53,450–456; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1993.50

年代:1993

数据来源: WILEY

摘要:

Objective: To determine the effect of the digoxin‐quinidine interaction on rate of in‐hospital digitalis toxicity.Methods: This was a prospective observational study over 9 months, set in two general medical wards. We studied consecutive patients (n= 141) who were receiving digoxin. Measurements included digitalis toxicity, defined by ECG criteria and resolution after stopping digoxin; all additional medications (including antiarrhythmics) continued. The observer was “blinded” to serum digoxin level and to concomitant drugs.Results: Digitalis toxicity rates were as follows: digoxin alone, 4.9% (5 of 101 patients); with amiodarone or verapamil, 5.0% (1 of 20 patients); with quinidine, 50% (10 of 20 patients) (p<0.01). No toxicity was seen at digoxin levels2.0 ng/ml: 4 of 8 patients and 7 of 11 patients, respectively. Independent relative risks and 95% confidence intervals (CI) of digitalis toxicity were as follows: serum digoxin, 9.1 (95% CI, 2.9 to 13.0); concurrent quinidine, 24.3 (95% CI, 3.4 to 124). There was a significant (p<0.01) interaction between concurrent quinidine, serum digoxin of 1.0 to 2.0 ng/ml, and digitalis toxicity.Conclusion: The digoxin‐quinidine interaction significantly increases digitalis toxicity, even in the therapeutic range of serum digoxin levels.Clinical Pharmacology and Therapeutics(1993)53,457—462; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1993.51

年代:1993

数据来源: WILEY