Concentrations Of Active Metabolite Research Articles

The natural history of tolerance to the benzodiazepines.

Dependence on benzodiazepines following continued use is by now a well-documented clinical phenomenon. Benzodiazepines differ in their dependence potential. The present studies were aimed at examining the possibility that differential rates of tolerance development might account for differences in dependence risk. Four studies are reported. The first three studies concerned normal subjects. The development of tolerance over a fifteen day period was demonstrated for three different benzodiazepines (ketazolam, lorazepam and triazolam) using two paradigms. Tolerance in terms of a reduction in effectiveness of a repeated given dose was most notable for the benzodiazepine with a medium elimination half-life (lorazepam) for physiological, behavioural and subjective measures. In the case of the drug with the longest elimination half-life (ketazolam) reduction in effectiveness could only be assumed to be occurring if account was taken of the steady increase in plasma concentrations of active metabolites. For this drug it seemed that the physiological measures were those most likely to demonstrate the development of tolerance. Although triazolam showed few significant drug effects on this paradigm (testing being 12 hours after ingestion of this short half-life benzodiazepine), tolerance was seen to develop on some subjective measures. Using an alternative method of testing tolerance, assessing responses to a diazepam challenge dose, a high degree of tolerance on two-thirds of the measures was observed in subjects when pretreated with the benzodiazepine with the most marked accumulation of active metabolites (ketazolam). The other two drugs also led to tolerance development on a range of measures; this was more marked for lorazepam than triazolam. Blunting of the growth hormone response to diazepam was the most sensitive and reliable method of detecting tolerance to the benzodiazepines. Symptoms on discontinuation of the two weeks' intake of the benzodiazepines were marked for all the drugs but unrelated to either the tolerance induced or the elimination half-life of the particular drug. A further clinical study revealed that tolerance persisted in a group of long-term benzodiazepine users for between four months and two years following complete abstinence from the drug. These patients appeared to be less affected by diazepam in terms of its commonly observed subjective effects, regardless of their original medication. These ex-long-term users of benzodiazepines were, however, more likely to manifest two specific types of effects--immediate 'symptom' reduction and exacerbation of 'withdrawal symptoms' over the subsequent week.(ABSTRACT TRUNCATED AT 400 WORDS)

Ara-C in plasma and ara-CTP in leukemic cells after subcutaneous injection and continuous intravenous infusion of ara-C in patients with acute nonlymphoblastic leukemia.

Six patients with acute nonlymphoblastic leukemia (ANLL) were treated sequentially with one subcutaneous (SC) injection (50 mg/m2) and one 156 hour continuous intravenous (IV) infusion (100 mg/m2/d) of 1-beta-D-arabinofuranosylcytosine (ara-C) with an interval of 12 hours. Leukemic cells were isolated from venous blood samples. The intracellular concentration of ara-C 5'-triphosphate (ara-CTP) was determined by high-performance liquid chromatography, and in two of the patients the plasma concentration of ara-C was determined by radioimmunoassay. A rapid biphasic elimination of the drug from plasma with an initial half-life of 18 minutes was seen after SC injection. After about 1.5 hours, the concentration was lower than that obtained at steady-state during continuous IV infusion. In the leukemic cells, the concentration of ara-CTP was higher after SC injection than during continuous IV infusion for about five hours. The mean half-life was 2.1 hours. Judging from the intracellular concentration of ara-CTP, considered to be the active metabolite, the results suggest that SC administration of ara-C can mimic continuous IV infusion if the dose interval is reduced from the traditional 12 hours to four to six hours. The results of this study emphasize the differences between the plasma pharmacokinetics of the parent drug and the concentration of the active metabolite in leukemic cells.

Kinetics of drug action: An overview

The intensity and time course of action of directly and reversibly acting drugs are related to and determined largely by the time course of drug and active drug metabolite concentrations in the body. When the pharmacokinetics and the concentration-effect relationship of a drug are known, it is often possible to predict the temporal pattern of its pharmacologic effect(s), including the maximum intensity and duration of action. Sites of action may not be immediately accessible to a drug even if it is injected intravenously; this may be reflected by a gradual increase in the intensity of effect despite decreasing drug concentrations in plasma, with maximum effects occurring later than maximum drug concentrations in plasma. Pharmacologic effects may persist well beyond the time when drug concentrations in plasma are no longer determinable; this is often caused by localization of the drug in an extravascular compartment. Drug distribution kinetics, pharmacologically active metabolites, and development of functional (as opposed to metabolic) tolerance may be responsible for time-dependent changes in drug concentration—pharmacologic effect relationships. Interindividual differences in patients' response to drug therapy may have a pharmacokinetic basis, a pharmacodynamic basis, or both. In clinical assessments of pharmacologic response, it is important to measure the therapeutically relevant effect, to determine interindividual and intraindividual variability, and to explore the possible influence of underlying diseases and other physiologic variables on drug concentration-effect relationships.

Oral 6-mercaptopurine in childhood leukemia: Parent drug pharmacokinetics and active metabolite concentrations

6-Mercaptopurine (6MP) pharmacokinetics and red blood cell 6-thioguanine nucleotide (TGN) concentrations were studied in 19 children receiving remission maintenance treatment for lymphoblastic leukemia. There was a high interpatient variation in all the pharmacokinetic parameters measured. The pharmacokinetic parameters measured in two children who subsequently had relapses were within the 95% confidence limits of the 17 other children. There was no difference in 6MP pharmacokinetic parameters with respect to neutropenia either after or before the study. The children who developed neutropenia 10 to 19 days after study had significantly higher TGN concentrations (U = 8; P less than 0.001) and had spent a longer time receiving reduced 6MP dosage in the 12 weeks before the study (U = 19.5; P less than 0.025). TGN concentrations are a better index of a child's ability to form active cytotoxic metabolites than 6MP dose or plasma concentrations.

Bromazepam and Diazepam in Generalized Anxiety

In a double-blind, placebo-controlled study, 48 anxious outpatients with a primary diagnosis of generalized anxiety disorder were randomly assigned to 4 weeks of treatment with bromazepam (18 mg/day), diazepam (15 mg/day), or placebo, after a 1-week washout period. From week 1 onward both active drugs were superior to placebo in relieving anxiety symptoms. Bromazepam was found to be significantly more effective than diazepam with respect to the somatic anxiety factor and the total score for the Hamilton Anxiety Rating Scale and the fear/anxiety factor of the Patient's Self-Rating Symptom Scale. Plasma concentrations of diazepam plus active metabolites were correlated significantly (r = 0.60, p less than 0.05) with the percentage reduction in self-rating anxiety scores. Bromazepam plasma concentration measurements showed greater variability than those of diazepam and were not found to be correlated significantly with clinical response. It is suggested that the use of strict diagnostic criteria (1978 draft of the third edition of Diagnostic and Statistical Manual of Mental Disorders), adequate sample sizes, and a 4-week study period gave increased sensitivity for the detection of significant differences between the two benzodiazepines.

Enalapril maleate and a lysine analogue (MK-521) in normal volunteers; relationship between plasma drug levels and the renin angiotensin system.

1 Two single doses of 10 mg each of the converting enzyme inhibitor enalapril maleate or MK-421 and of its lysine analogue (MK-521) were administered p.o. to twelve male volunteers. 2 The active diacid metabolite of MK-421 and the lysine analogue were determined by radioimmunoassay and MK-421 by the active metabolite method following in vitro hydrolysis. 3 Peak serum levels of MK-421, active metabolite and lysine analogue were reached within 1, 3 to 4, and 6 h respectively. Practically all MK-421 had disappeared from serum within 4 h. 4 A close correlation between percent inhibition of plasma converting enzyme activity and the serum concentration of active metabolite was observed ( r = 0.98, n = 171, P less than 0.001). Similarly, converting enzyme blockade as expressed by the ratio plasma angiotensin II/angiotensin I was closely correlated with serum active metabolite levels (r = 0.93, n = 15, P less than 0.001).

Metabolic disposition of cephalothin and deacetylcephalothin in children and adults: Comparison of high‐performance liquid chromatographic and microbial assay procedures

A highly specific method utilizing ion‐pair extraction and high‐pressure liquid chromatography has been developed for the analysis of cephalothin and deacetylcephalothin in biological specimens. Kinetic data obtained in children and adults were used to compare this method of analysis with microbial assay procedures. In this study serum elimination curves were developed following the intravenous administration of cephalothin to adults (5 to 37.5 mg/kg) and children (10 to 25 mg/kg). The elimination half‐life (t½ of cephalothin from serum was 13.5 ± 3.2 min in adults and 18.6 ± 4.6 min in children (p < 0.05). The mean KEL in adults was 3.15 ± 0.2 hr‐1 and 2.35 ± 0.51 hr‐1 in children; the specific VD in adults was 0.21 ± 0.03 Llkg as compared to 0.93 ± 0.15 Llkg in children. The primary metabolite of cephalothin, deacetylcephalothin, was present in sera and urine obtained from adult subjects. Approximately 25% of the cephalothin dose administered was eliminated in urine as deacetylcephalothin. Significant differences were observed between microbial and high‐pressure liquid chromatographic assay procedures in that the former estimated higher concentrations of cephalothin in urine specimens, probably due to the presence of high concentrations of deacetylcephalothin or other active metabolites. The rapid plasma clearance of cephalothin suggests that clinical regimens using 4‐to 6‐hr dosage intervals may result in drug levels which are below the minimum inhibitory concentration of most susceptible organisms for approximately 50% of each treatment period.