This article reviews the metabolism and pharmacokinetics of ifosfamide and their implications for the cytostatic efficacy and toxicity pattern of this alkylating agent. Ifosfamide is a prodrug that requires biotransformation to become cytotoxic. It is a structural isomer of cyclophosphamide from which it differs only in having the chlorethyl functions on different nitrogen atoms. This causes a considerable change in initial metabolism, although overall metabolism remains the same. Beside the formation of 4-hydroxy-ifosfamide (‘activated ifosfamide’), a second pathway with liberation of chloroacetaldehyde exists. Therefore, less activated drug is formed than during cyclophosphamide metabolism. This fact may well explain why higher doses of ifosfamide are required during treatment.

Ifosfamide Clinical Pharmacokinetics

Information on antibiotic therapeutics in laboratory species, especially in rodents and rabbits, is reviewed. A number of areas are considered: interference by antibiotics with an experiment, antibiotic toxicity, routes of administration, effects of formulation on bioavailability, antibiotic prophylaxis, use of combinations of antibiotics, misuse of antibiotics, regulatory approval for antibiotic use in animals, sources of information on antibiotic indications and dose, and extrapolation of dose information from other species.

https://lan.sagepub.com/content/29/1/16.full.pdf

Antibiotic therapeutics in laboratory animals

Summary Plasma concentrations and urinary excretion rates of cyclophosphamide and its total metabolites were measured after iv administration of 500- to 1000-mg doses of radiolabeled cyclophosphamide to four patients The data obtained before and after phenobarbital treatment were analyzed pharmacokinetically with the use of a two-compartment open model Phenobarbital had no quantitatively important effects on the distribution and renal excretion of cyclophosphamide The rate of biotransformation of the inactive precursor to its total metabolites was increased 2- to 3-fold by phenobarbital However, because biotransformation is the predominant pathway of cyclophosphamide disposition, the total quantity of metabolites formed was only increased slightly by phenobarbital These observations, together with comprehensive data in the literature showing that phenobarbital has little effect on the chemotherapeutic properties of cyclophosphamide in several animal tumor systems, indicate that phenobarbital treatment should modify only slightly the efficacy and toxicity of cyclophosphamide in man

https://cancerres.aacrjournals.org/content/canres/32/12/2761.full.pdf

Phenobarbital effects on cyclophosphamide pharmacokinetics in man.

Publication of the mathematics of accumulation in the one compartment open model by Widmark and Tandberg (1924) and the two papers on the two-compartment open model by the organizer of this conference, Professor Torsten Teorell (1937), were the origins of pharmacokinetics. Many of us who have studied the literature of pharmacokinetics have been amazed at the insight and foresight embodied in Professor Teorell’s two papers. The classical one- and two-compartment open linear models have withstood the test of time, achieved accurate assessment of rates of absorption, metabolism, and excretion when applied to certain specific drugs, and been very useful for predictive purposes. Undoubtedly in the future these classical models will continue to be as useful as they have in the past. These classical pharmacokinetics models are based upon systems of linear differential equations, which may conveniently be integrated using Laplace transforms. Kinetic linearity was defined by Kruger-Thiemer (1968a) as direct proportionality of transfer rates to concentrations or concentration differences.

/pdf/a-modern-view-of-pharmacokinetics-sqk30xi8uc.pdf

A modern view of pharmacokinetics

There are two facets to the problem of the biochemical and physical aspects of drug actions, the influence of drugs on the body and the influence of the body on drugs. In the past, pharmacology has emphasized the action of drugs on the living organism. But to be effective, a substance must have characteristics that allow it to reach its site of action in adequate concentration and to remain there for a suitable period of time. For this reason, we become concerned with the physical and biochemical factors that determine the duration of drug action. About 25 years ago, when I first became interested in the fate of drugs, I felt like the bat in Aesop's fable. Journals of pharmacology showed considerable reluctance in associating themselves with this "biochemical" topic, while biochemical journals refused these "drug" papers outright. But over the years pharmacology has broadened and these sort of studies

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=JAMA&articleId=336294&pdfFileName=jama_202_7_016.pdf

Physicochemical and biochemical aspects of pharmacology.

Studies in recent years have disclosed two types of drug interaction which may be important in drug therapy:(1) Administration of one drug can speed up the metabolism of another drug Animal experiments show that this results from the ability of drugs to induce the synthesis of drug-metabolizing enzymes in liver microsomes This effect has considerable importance in pharmacologic and toxicologic studies carried out in animals, and recent work indicates that it may explain altered therapeutic responses observed in some patients when they receive several drugs at the same time Substances present in the environment, such as the insecticides chlordane and DDT, have been shown in animals to stimulate drug-metabolizing enzymes in liver, but the significance of this observation for man is not known Drugs which stimulate drug metabolism also enhance the hydroxylation of testosterone, estradiol, progesterone and cortisol by enzymes in liver microsomes Further research is required to establish the physiological importance of this interaction of drugs in steroid metabolism(2) One drug may inhibit the metabolism of another drug and thus intensify and prolong its pharmacologic action Although this effect is well documented in animals, recent reports suggest that this may also be important in man For instance, the action of coumarin anticoagulants can be potentiated by administration of certain drugs which inhibit their metabolism Monoamine oxidase inhibitors block the metabolism of certain sympathomimetic amines and this can lead to serious side-effects Thus, hypertensive crises have been observed in patients receiving monoamine oxidase inhibitors who have eaten cheese with a high tyramine content

A H Conney

Papers

Enzyme stimulation and inhibition in the metabolism of drugs.