Sex-dependent pharmacokinetics of S(−)-hydroxyhexamide, a pharmacologically active metabolite of acetohexamide, in rats

ABSTRACT Bis(isopropyloxymethylcarbonyl) 9-R-(2-phosphonomethoxypropyl)adenine [bis(POC)PMPA] has been identified as a novel prodrug of PMPA. The anti-human immunodeficiency virus activity of bis(POC)PMPA was >100-fold greater than that of PMPA in both an established T-cell line and primary peripheral blood lymphocytes. This improved efficacy was shown to be due to a rapid intracellular uptake of the prodrug resulting in an increased intracellular accumulation of PMPA diphosphate (PMPApp), the pharmacologically active metabolite. PMPApp levels in bis(POC)PMPA-treated cells exceeded by >1,000-fold the levels seen in cells treated with unmodified PMPA in both resting and activated peripheral blood lymphocytes. Significant differences in the intracellular catabolism of PMPA metabolites were noted between the resting and activated lymphocytes. The half-life for the disappearance of PMPApp, derived from either bis(POC)PMPA or PMPA, was 12 to 15 h in the activated lymphocytes and 33 to 50 h in the resting lymphocytes. This long persistence of PMPApp, particularly in resting lymphocytes, may be unique to the nucleoside phosphonate analogs and indicates that effective levels of the active metabolite can be achieved and maintained with relatively infrequent administration of the parent drug.

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Determination of tricyclic antidepressant, clomipramine (Anafranil), in plasma by a specific radioimmunoassay procedure.

Clinical Chemistry ◽

10.1093/clinchem/24.1.36 ◽

1978 ◽

Vol 24 (1) ◽

pp. 36-40 ◽

Cited By ~ 11

Author(s):

G F Read ◽

D Riad-Fahmy

Keyword(s):

Bovine Serum Albumin ◽

Active Metabolite ◽

Antidepressant Drug ◽

Tricyclic Antidepressant ◽

Chromatographic Purification ◽

Throughput Rate ◽

Specific Radioimmunoassay ◽

Pharmacologically Active ◽

Good Agreement

Abstract A radioimmunoassay is reported for the tricyclic antidepressant drug, clomipramine (Anafranil, Geigy). Antisera generated in rabbits to clomipramine conjugated to bovine serum albumin at positions 10 and 11 were specific, cross reacting less than 5% with the pharmacologically active metabolite, desmethylclomipramine. Specificity was confirmed by the good agreement in titres observed when the samples were assayed with and without a pre-assay thin-layer chromatographic purification. Intra- and inter-assay variations were less than 8 and 13%, respectively, with a sensitivity of 175 ng/liter. Results obtained agreed well with those reported by other groups using double radioisotope derivative assays. The method has a high throughput rate, one technician can assay 200 samples in duplicate in a working week; and it is sufficiently precise, sensitive, and specific for use in routine minitoring of the drug in plasma and for checking patient compliance with dosage regimen.

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Identification of a Pharmacologically Active Metabolite of Mycophenolic Acid in Plasma of Transplant Recipients Treated with Mycophenolate Mofetil

Clinical Chemistry ◽

10.1093/clinchem/45.3.419 ◽

1999 ◽

Vol 45 (3) ◽

pp. 419-422 ◽

Cited By ~ 108

Author(s):

Ekkehard Schütz ◽

Maria Shipkova ◽

Victor W Armstrong ◽

Eberhard Wieland ◽

Michael Oellerich

Keyword(s):

Mycophenolate Mofetil ◽

Mycophenolic Acid ◽

Active Metabolite ◽

Transplant Recipients ◽

Pharmacologically Active

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Hepatic Microsomal Thiol Methyltransferase Is Involved in Stereoselective Methylation of Pharmacologically Active Metabolite of Prasugrel

Drug Metabolism and Disposition ◽

10.1124/dmd.114.057661 ◽

2014 ◽

Vol 42 (7) ◽

pp. 1138-1145 ◽

Cited By ~ 9

Author(s):

Miho Kazui ◽

Katsunobu Hagihara ◽

Takashi Izumi ◽

Toshihiko Ikeda ◽

Atsushi Kurihara

Keyword(s):

Active Metabolite ◽

Thiol Methyltransferase ◽

Pharmacologically Active

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An iminium ion metabolite hampers the production of the pharmacologically active metabolite of a multikinase inhibitor KW-2449 in primates: irreversible inhibition of aldehyde oxidase and covalent binding with endogenous proteins

Biopharmaceutics & Drug Disposition ◽

10.1002/bdd.2123 ◽

2018 ◽

Vol 39 (3) ◽

pp. 164-174 ◽

Cited By ~ 4

Author(s):

Jun Hosogi ◽

Rui Ohashi ◽

Hiroshi Maeda ◽

Kazuhiro Fujita ◽

Junko Ushiki ◽

...

Keyword(s):

Active Metabolite ◽

Covalent Binding ◽

Aldehyde Oxidase ◽

Multikinase Inhibitor ◽

Irreversible Inhibition ◽

Iminium Ion ◽

Endogenous Proteins ◽

Pharmacologically Active

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Population Pharmacokinetics of Clozapine and Norclozapine and Switchability Assessment between Brands in Uruguayan Patients with Schizophrenia

BioMed Research International ◽

10.1155/2019/3163502 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Ismael Olmos ◽

Manuel Ibarra ◽

Marta Vázquez ◽

Cecilia Maldonado ◽

Pietro Fagiolino ◽

...

Keyword(s):

Active Metabolite ◽

Smoking Status ◽

Antipsychotic Agent ◽

Comparable Efficacy ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Uv Detector ◽

Caffeine Consumption ◽

Apparent Clearance ◽

Pharmacologically Active

Clozapine (CZP) is an atypical antipsychotic agent commonly used in the treatment of schizophrenia. It is metabolized primarily by CYP1A2 enzyme, yielding a pharmacologically active metabolite, norclozapine (NCZP). Significant intra- and interindividual pharmacokinetic (PK) variability for CZP and NCZP has been observed in routine therapeutic drug monitoring. So the goal of this study was to evaluate the magnitude and variability of concentration exposure to CZP and its active metabolite NCZP on pharmacokinetic parameters in Uruguayan patients with schizophrenia with a focus on covariates such as cigarette smoking, age, sex, caffeine consumption, brands available of CZP, and comedication using population PK (PPK) modeling methodologies. Patients with a diagnosis of schizophrenia treated with brand-name CZP (Leponex®) for more than a year were included in the study. Then these patients were switched to the similar brand of CZP (Luverina®). Morning predose blood samples for determination of CZP and NCZP using a HPLC system equipped with a UV detector were withdrawn on both occasions at steady state and under the same comedication. Ninety-eight patients, 22 women and 76 men, took part in the study. Mean ± standard deviation for CZP and NCZP concentration was 421 ± 262 ng/mL and 275 ± 180 ng/mL, respectively. After covariate evaluation, only smoking status remained significant in CZP apparent clearance, inducing a mean increment of 32% but with no clinical impact. The results obtained with the two brands of CZP should ensure comparable efficacy and tolerability with the clinical use of either product. Smoking was significantly associated with a lower exposure to CZP due to higher clearance. The results obtained with the two brands commercialized in our country hint a bioequivalence scenario in the clinical setting.

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The Mechanism of Action of Cyclophosphamide and Its Consequences for the Development of a New Generation of Oxazaphosphorine Cytostatics

Scientia Pharmaceutica ◽

10.3390/scipharm88040042 ◽

2020 ◽

Vol 88 (4) ◽

pp. 42

Author(s):

Georg Voelcker

Keyword(s):

Mechanism Of Action ◽

Active Metabolite ◽

Dna Alkylation ◽

In Vivo Metabolism ◽

Pharmacologically Active ◽

New Generation ◽

Anti Tumor Activity ◽

Oxazaphosphorine Cytostatics

Although cyclophosphamide (CP) has been used successfully in the clinic for over 50 years, it has so far not been possible to elucidate the mechanism of action and to use it for improvement. This was not possible because the basis of the mechanism of action of CP, which was found by lucky coincidence, is apoptosis, the discovery of which was honored with the Nobel Prize only in 2002. Another reason was that results from cell culture experiments were used to elucidate the mechanism of action, ignoring the fact that in vivo metabolism differs from in vitro conditions. In vitro, toxic acrolein is formed during the formation of the cytotoxic metabolite phosphoreamidemustard (PAM), whereas in vivo proapoptotic hydroxypropanal (HPA) is formed. The CP metabolites formed in sequence 4-hydroxycyclophosphamide (OHCP) are the main cause of toxicity, aldophosphamide (ALDO) is the pharmacologically active metabolite and HPA amplifies the cytotoxic apoptosis initiated by DNA alkylation by PAM. It is shown that toxicity is drastically reduced but anti-tumor activity strongly increased by the formation of ALDO bypassing OHCP. Furthermore, it is shown that the anti-tumor activity against advanced solid P388 tumors that grow on CD2F1 mice is increased by orders of magnitude if DNA damage caused by a modified PAM is poorly repairable.

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