摘要:

Summary:Because of the binding of chloroquine to various tissue components and the lysosomotropism of chloroquine, its pharmacokinetics exhibit large apparent volumes of distribution, partial recoveries in urine, and persistence of low blood levels. These complexities have been reinvestigated with modern, highly sensitive methods for the determination of the drug and its major metabolite, desethylchloroquine, which reaches blood levels of about one‐third those of the parent drug and constitutes about one‐fifith of the 56% of drug accounted for by urinary recovery. Bioavailability is essentially complete, apparent volumes of distribution range up to 800 L/kg, and the pharmacokinetic data are generally accomodated by three compartment models. Half‐lives for the terminal component are 1 to 2 months, but the terminal phases may be of minor importance in effectiveness. Dose dependence, i.e. nonlinearity in the relationship of dose and area under the plasma curve, apparently is not a factor. Some of the most recent studies, designed to provide a rationale for safer parenteral administration, have made possible computer‐generated optimal infusion regimens. Revised schedules of loading and maintenance oral doses for antimalarial therapy have resulted from other pharmacokinetic studies. The in vitro antimalarial potencies of the two optical enantiomers of chloroquine are identical, but recent data suggest stereospecific differences in metabolic rates and renal secretion mechanisms. The marked uptake of chloroquine into the acidic food vacuoles of parasites resident in erythrocytes is assumed to underlie its antimalarial action, but mechanisms other than the previously assumed alkalization of the vacuole, possibly inhibition of phospholipid metabolism, now seem more likely to inhibit parasite function. Mild immunosuppression with inhibition of the elaboration of rheumatoid factor and acute phase reactants is a likely mechanism for the beneficial effects of chloroquine in rheumatoid arthritis. Blockade of interleukin‐1 release could lead to these effects and is one of the few instances in which the low chloroquine levels attainable in human serum can be shown to affect immunological reactions.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary:Fifteen cancer patients were studied following repeated courses of doxorubicin (12‐44 mg/m2) (together with other anticancer agents) to consider the possibility of enhanced metabolism as a cause of the previously reported reduction in doxorubicin plasma concentrations with repeated courses. Plasma doxorubicin and doxorubicinol concentrations were measured by a modified high‐performance liquid chromatography/fluorescence method. The results presented confirmed the significant decline in doxorubicin plasma concentration‐dose ratios measured 3 h after the 1‐h infusion. Although the degree of this reduction varied markedly between patients, it was shown not to be associated with a rise in the plasma concentration‐dose ratio of the major metabolite doxorubicinol or with altered renal and/or hepatic function, which may have influenced disposition. Alternative mechanisms that might explain the reduction in doxorubicin concentrations, such as increased doxorubicin clearance or volume of distribution, were not considered in the present study.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary:A method is presented for the determination of valproate (VPA) in ˜40 &mgr;l erythrocyte concentrations. Valproate partition between plasma proteins, ultrafiltrate, and erythrocytes at various concentrations was studied in vitro and in vivo. Partition ratios depended on VPA concentration in whole blood and the ratio of erythrocytes/ultrafiltrate, which increased with rising concentrations in the ultrafiltrate fraction. Shifts in ratios were studied by expanding the ultrafiltrate fraction of VPA‐spiked blood. It appeared that VPA delivery to the expanded ultrafiltrate compartment originated in a disproportionately large part from erythrocytes. In vivo the half‐life of VPA in the erythrocyte fraction was 0.7 h, whereas in the ultrafiltrate fraction and proteinbound fraction half‐lives of 2 and 5 h were observed. It is concluded that for VPA in relation to erythrocytes a “last‐come‐first‐go” system is plausible.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary:Phenytoin (DPH) partition between the three main blood compartments, i.e., plasma proteins, erythrocytes, and plasma water, was studied at various concentrations in vitro and in vivo. In vitro, the partition ratio of DPH in a system of erythrocytes in plasma water was 4.5 at concentrations between 0.8 and 100.8 &mgr;g DPH/ml. In vitro in whole blood (hence, in the presence of plasma proteins), this ratio was approximately 3.9. At 38°C, blank erythrocytes were already in equilibrium with DPH‐spiked plasma 3 min after contact, whereas at 20°C, equilibration took 10 minutes or more. By adding blank ultrafiltrate to blood containing DPH, DPH concentrations of blood compartments shifted. It appeared that with the added blank ultrafiltrate, DPH was delivered overproportionally from erythrocytes and less from the protein fraction. In vivo, the elimination half‐life of DPH in erythrocytes was 21.4 h and in plasma proteins 67.9 h. These results are similar to those obtained with valproate. It is concluded that erythrocytes have a low affinity for DPH. Their high‐capacity transport system, having a “last‐come‐first‐go” mechanism, plays a quantitatively important role in the transport of DPH.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary:Hydrocortisone (HC) distribution over the three main components of blood, i.e., plasma water, plasma proteins, and erythrocytes, was studied in vitro at various HC concentrations in plasma, in a suspension of washed erythrocytes in plasma water, and in whole blood. The distribution ratio of HC in the system of erythrocytes in plasma water was 2.1 when HC, 0.18‐10.8 &mgr;g/ml, was added. In whole blood, however, this ratio was 2.4 for the same concentration range. In the HC range of 0.18‐0.68 &mgr;g/ml of whole blood, the uptake percentage of HC by erythrocytes increased from about 16 to 28% of the amount of HC added. By adding blank ultrafiltrate to HC‐enriched blood, it appeared that the erythrocyte fraction released HC in overproportional quantities compared with the release by plasma proteins. Similar findings have previously been reported regarding the drugs valproic acid and phenytoin. Migration of HC from HC‐spiked plasma to blank erythrocytes reached an equilibrium within 5 min.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary:Theophylline concentrations in plasma and urine were determined during maintenance treatment in nine healthy volunteers during one dosage interval before and after 10 days of simultaneous treatment with pentobarbital (100 mg each night). During the pentobarbital period, total plasma clearance of theophylline increased by 40% (range −4‐79%), whereas renal clearance remained unchanged. It is concluded that therapeutic doses of pentobarbital induce the metabolism of theophylline with marked interindividual variation.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary:The pharmacokinetic interaction between the gastrointestinal motility‐stimulating substance cisapride and the H2‐antagonist cimetidine was examined in 8 healthy volunteers (25 ± 2 years of age). Steady‐state kinetics of both substances were investigated after separate 1‐week treatments of oral cisapride, 10 mg t.i.d., cimetidine, 400 mg t.i.d., and the two drugs combined. Cimetidine increased the cisapride peak plasma concentration from 58 ± 25 ng/ml to 84 ± 19 ng/ml (p = 0.01) and AUC0‐24from 509 ± 289 ng/ml • h to 738 ± 148 ng/ml • h (p = 0.02). Cisapride shortened the time to the peak concentration of cimetidine from 1.3 ± 0.6 h to 0.6 ± 0.2 h (p = 0.005) and reduced the cimetidine AUC0‐24from 11.0 ± 2.3 &mgr;g/ml • h to 9.0 ± 2.0 &mgr;g/ml • h (p = 0.05). It is concluded that cimetidine inhibits cisapride metabolism, whereas cisapride enhances the gastrointestinal absorption of cimetidine.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary:Eight patients are described who displayed excessive concentrations of nortriptyline, imipramine, or clomipramine on routine blood level monitoring. Under these conditions, the patients did not respond to the treatment. All patients were markedly improved when the daily dosage of the antidepressant was reduced with a simultaneous decrease of the blood concentrations. Among these eight patients, seven suffered from side‐effects, three were characterized as poor hydroxylators of debrisoquine, while three had concomitant treatment with a phenothiazine.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary:The study objective was to evaluate serum, peritoneal fluid, and appendix tissue concentrations of clindamycin using two differing clindamycin regimens. Patients age 16 years and older who were about to undergo appendectomies were randomly assigned to receive gentamicin 1.5 mg/kg every 8 h admixed with clindamycin 900 mg every 8 h (8‐h group) or clindamycin 600 mg every 6 h given separately (6‐h group). Doses of each regimen were given preoperatively. Serum, peritoneal fluid, and appendix tissue samples were obtained intraoperatively, and frozen at −70°C for gas chromatographic drug analysis. Twenty‐one patients were evaluated, 11 patients in the 8‐h group and 10 patients in the 6‐h group. Values are reported as means ± standard deviations. The values in the 8‐h group were 12.3 ± 14.1 &mgr;g/ml, 8.7 ± 3.9 &mgr;g/ml, and 9.8 ± 10.3 &mgr;g/g for serum, peritoneal fluid, and appendix tissue, respectively. The values in the 6‐h group were 9.7 ± 5.1 &mgr;g/ml, 5.8 ± 5.3 &mgr;g/ml, and 6.2 ± 4.9 &mgr;g/g for serum, peritoneal fluid, and appendix tissue, respectively. The 6‐h group received more doses preoperatively (1.8 ± 0.6) than the 8‐h group (1.2 ± 0.4; p < 0.05). No differences in penetration of clindamycin into the serum, peritoneal fluid, and appendix tissue for the 8‐h group and the 6‐h group were noted. The study revealed a similarity in penetration of clindamycin into the serum, peritoneal fluid, and appendix tissue using either clindamycin 900 mg given by intermittent intravenous infusion every 8 h admixed with gentamicin or clindamycin 600 mg given every 6‐h separately.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary:The potential clinical usefulness of therapeutic drug monitoring (TDM) in neonates is discussed. The personnel performing neonatal TDM must be knowledgeable in the many clinical, analytical, and pharmacokinetic variables used for measuring drug concentrations to formulate rational, individualized dosing regimens. Examples of variables and their effects on TDM interpretations are given and some gaps in our knowledge are presented. The theoretical promise of neonatal TDM is contrasted with the practical realities.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID