The rationale fo the development of prodrugs relies upon delivery of higher concentrations of a drug to target cells compared to administration of the drug itself. In the last decades, numerous prodrugs that are enzymatically activated into anti-cancer agents have been developed. This review describes the most important enzymes involved in prodrug activation notably with respect to tissue distribution, up-regulation in tumor cells and turnover rates. The following endogenous enzymes are discussed: aldehyde oxidase, amino acid oxidase, cytochrome P450 reductase, DT-diaphorase, cytochrome P450, tyrosinase, thymidylate synthase, thymidine phosphorylase, glutathione S-transferase, deoxycytidine kinase, carboxylesterase, alkaline phosphatase, beta-glucuronidase and cysteine conjugate beta-lyase. In relation to each of these enzymes, several prodrugs are discussed regarding organ- or tumor-selective activation of clinically relevant prodrugs of 5-fluorouracil, axazaphosphorines (cyclophosphamide, ifosfamide, and trofosfamide), paclitaxel, etoposide, anthracyclines (doxorubicin, daunorubicin, epirubicin), mercaptopurine, thioguanine, cisplatin, melphalan, and other important prodrugs such as menadione, mitomycin C, tirapazamine, 5-(aziridin-1-yl)-2,4-dinitrobenzamide, ganciclovir, irinotecan, dacarbazine, and amifostine. In addition to endogenous enzymes, a number of nonendogenous enzymes, used in antibody-, gene-, and virus-directed enzyme prodrug therapies, are described. It is concluded that the development of prodrugs has been relatively successful; however, all prodrugs lack a complete selectivity. Therefore, more work is needed to explore the differences between tumor and nontumor cells and to develop optimal substrates in terms of substrate affinity and enzyme turnover rates fo prodrug-activating enzymes resulting in more rapid and selective cleavage of the prodrug inside the tumor cells.

Enzyme-Catalyzed Activation of Anticancer Prodrugs

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5% of hepatocytes with little or no alcohol consumption. Insulin ...

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Non-alcoholic fatty liver disease (NAFLD) - pathogenesis, classification, and effect on drug metabolizing enzymes and transporters.

Members of the family of B9 vitamins are commonly known as folates. They are derived entirely from dietary sources and are key one-carbon donors required for de novo nucleotide and methionine synthesis. These highly hydrophilic molecules use several genetically distinct and functionally diverse transport systems to enter cells: the reduced folate carrier, the proton-coupled folate transporter and the folate receptors. Each plays a unique role in mediating folate transport across epithelia and into systemic tissues. The mechanism of intestinal folate absorption was recently uncovered, revealing the genetic basis for the autosomal recessive disorder hereditary folate malabsorption, which results from loss-of-function mutations in the proton-coupled folate transporter gene. It is therefore now possible to piece together how these folate transporters contribute, both individually and collectively, to folate homeostasis in humans. This review focuses on the physiological roles of the major folate transporters, with a brief consideration of their impact on the pharmacological activities of antifolates.

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Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues.

Summary The human pharmacology of cyclophosphamide was investigated in 26 patients who received cyclophosphamide 14 C in doses of 6 to 80 mg/kg i.v. Levels of the intact drug in plasma and urine and excretion of 14 C label in breath and stools were determined by liquid scintillation counting. Plasma and urine alkylating activity was measured by reaction with 4-(4-nitrobenzyl)pyridine. Protein binding of cyclophosphamide and plasma alkylating metabolites were determined by plasma ultrafiltration. Injected cyclophosphamide distributed rapidly into 64% of body weight, and plasma cyclophosphamide half-life in patients without prior drug exposure was 6.5 hr. Not more than 20% of injected cyclophosphamide was excreted intact in urine at any dose level. Plasma alkylating metabolites were 56% bound to plasma proteins. After a 40-mg/kg dose, peak unbound alkylating activity averaged 13.3 mµmoles/ml, and in most patients at this dose alkylating activity in the plasma was measurable for 24 hr. Sixty-eight % of injected 14 C label was excreted in urine. Breath and fecal excretion were negligible. In a regimen of five consecutive daily cyclophosphamide administrations, cyclophosphamide half-life was shorter and peak alkylating levels were constantly higher on the 5th day than on the 1st day. Prior patient treatment with allopurinol resulted in significantly longer cyclophosphamide half-life, but concomitant prednisolone treatment had no effect. The effect of hepatic metastases on cyclophosphamide metabolism was unclear. Moderate renal failure in one patient resulted in prolonged retention of alkylating materials in plasma and severe toxicity. Although patients with and without prior exposure to microsomal enzyme-inducing drugs demonstrated marked variation in plasma cyclophosphamide half-life and peak alkylating levels, the total concentration × time product remained relatively constant for a given cyclophosphamide dose, suggesting that alterations in the rate of cyclophosphamide metabolism by drugs or liver metastases in the absence of renal failure will not change toxicity or therapeutic effect.

https://cancerres.aacrjournals.org/content/canres/33/2/226.full.pdf

Clinical pharmacology of cyclophosphamide.

David C. Pryde,* Deepak Dalvie, Qiyue Hu, Peter Jones, R. Scott Obach, ) and Thien-Duc Tran WorldWide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, England, Pharmacokinetics, Dynamics andMetabolism, Pfizer Global Research andDevelopment, 10628 ScienceCenterDrive, La Jolla, California 92121, WorldWide Medicinal Chemistry, Pfizer Global Research and Development, 10628 Science Center Drive, La Jolla, California 92121, and ) Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340

Aldehyde oxidase: an enzyme of emerging importance in drug discovery.

HUMAN LIVER ALDEHYDE OXIDASE (ALDEHYDE: O(2) oxidoreductase, EC 1.2.3.1) has been purified 60-fold and some of its properties studied. Like aldehyde oxidase from other mammalian species, human liver aldehyde oxidase is an enzyme with dual substrate specificity, possessing the ability to catalyze not only the oxidation of aldehydes to the corresponding carboxylic acids, but also the hydroxylation of a number of nonaldehydic heterocyclic compounds; its relative activity towards the latter group of substrates is low, however, when compared with that of liver aldehyde oxidase from rabbit and guinea pig. When the aromatic aldehyde benzaldehyde is used as substrate, human liver aldehyde oxidase, like the rabbit enzyme, is strongly inhibited by menadione, estradiol-17beta, antimycin A, Triton X-100, and N-alkylphenothiazines; the human enzyme differs from the rabbit enzyme, however, in being relatively insensitive to oligomycin and Amytal. Like the rabbit enzyme, the human enzyme can catalyze the 3-hydroxylation of phenazine methosulfate (PMS) and the 6-hydroxylation of N-methylnicotinamide (NMN). With the rabbit enzyme, however, the aerobic hydroxylation of these substrates proceeds by a conventional mechanism, while with the human enzyme, the aerobic hydroxylation of PMS and NMN is anomalous in that the reaction is inhibited only by agents with affinity for the substrate-binding site, such as cyanide and N-alkylphenothiazines, and not by agents which inhibit the "internal electron transport chain" of the enzyme, such as menadione and diethylstilbestrol. This mode of oxidation appears to be unique to substrates with a positively charged quaternary nitrogen; the hydroxylation of other nonaldehydic heterocyclic substrates for the human enzyme is sensitive to conventional aldehyde oxidase inhibitors.

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Human Liver Aldehyde Oxidase: Differential Inhibition of Oxidation of Charged and Uncharged Substrates

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David G. Johns

Papers

Human Liver Aldehyde Oxidase: Differential Inhibition of Oxidation of Charged and Uncharged Substrates

The renal excretion of folic acid.