Physiologically based pharmacokinetic modelling of the three‐step metabolism of pyrimidine using¹³C‐uracil as anin vivoprobe

Abstract

AimsApproximately 80% of uracil is excreted as b -alanine, ammonia and CO 2 via three sequential reactions. The activity of the first enzyme in this scheme, dihydropyrimidine dehydrogenase (DPD), is reported to be the key determinant of the cytotoxicity and side-effects of 5-fluorouracil. The aim of the present study was to re-evaluate the pharmacokinetics of uracil and its metabolites using a sensitive assay and based on a newly developed, physiologically based pharmacokinetic (PBPK) model. Methods [2-13 C]Uracil was orally administrated to 12 healthy males at escalating doses of 50, 100 and 200 mg, and the concentrations of [2-13 C]uracil, [2-13 C]5,6-dihydrouracil and b -ureidopropionic acid (ureido-13 C) in plasma and urine and 13 CO 2 in breath were measured by liquid chromatography-tandem mass spectrometry and gas chromatograph-isotope ratio mass spectrometry, respectively. Results The pharmacokinetics of [2-13 C]uracil were nonlinear. The elimination half-life of [2-13 C]5,6-dihydrouracil was 0.9-1.4 h, whereas that of [2-13 C]uracil was 0.2-0.3 h. The AUC of [2-13 C]5,6-dihydrouracil was 1.9-3.1 times greater than that of [2-13 C]uracil, whereas that of ureido-13 C was 0.13-0.23 times smaller. The pharamacokinetics of 13 CO 2 in expired air were linear and the recovery of 13 CO 2 was approximately 80% of the dose. The renal clearance of [2-13 C]uracil was negligible. ConclusionA PBPK model to describe 13 CO 2 exhalation after orally administered [2-13 C]uracil was successfully developed. Using [2-13 C]uracil as a probe, this model could be useful in identifying DPD-deficient patients at risk of 5-fuorouracil toxicity.

Physiologically based pharmacokinetic modelling: a sound mechanistic basis is needed

“…Given the complexity of PBPK modelling, more use has been made of partial PBPK models or semimechanistic models. An example appears in the current issue of the Journal , in which Ito et al [13] describe a recirculating hepatic clearance model that they used to describe the CO 2 exhalation rate after administration of uracil [14]. However, the physiological component of the model in this application is minimal, and it is doubtful whether it is necessary.…”

IR Low‐Temperature Matrix and ab Initio Study on β‐Alanine Conformers

“…In vivo, the pyrimidine degradation pathway is the main route for the synthesis of balanine in human beings. [22] b-Alanine is a structural analogue of GABA (g-aminobutyric acid) and glycine, which are the major inhibitory neurotransmitters in the central nervous system. It has been suggested that b-alanine itself might function as a neurotransmitter since it is an agonist of both the glycine and GABA A receptors.…”

The Use of 13C–Erythromycin as an in vivo Probe to Evaluate CYP3A-mediated Drug Interactions in Rats

“…22,29 The effects of concomitant drugs on the intrinsic metabolic clearance of EM (CL m,int ) are expressed as follows, using the metabolic factor (M-factor), which can differ among the control (M-factor = 1) and treatment groups:…”

“…Quantitative methods to analyze breath response have been investigated using 14 C-or 13 C-labeled compounds for the assessment of metabolic activity [20][21][22] and gastric emptying. 23 For the assessment of CYP3A activity using 14 C-and 13 C-EBTs, C max , T max , pulmonary CO 2 excretion (% dose/h), and cumulative recovery of CO 2 (% dose) were evaluated as indices of their correlation with drug clearances.…”

“…In our previous study of 13 C-uracil breath test, a PBPK model was developed for describing the time profiles of the breath response. 22 In this study, we evaluated the use of 13 C-EM as an in vivo probe for assessing the alterations of CYP3A activity by drug interactions in rats. 13 C-EBT was performed without or with concomitant drugs, that is, ketoconazole (KCZ) and dexamethasone (DEX), which are known as an inhibitor and an inducer of CYP3A, respectively.…”