Jun-ichi Kunizaki

Pharmacokinetic Modelling of [2-13C]Uracil Metabolism in Normal and DPD-Deficient Dogs

A physiologically based pharmacokinetic (PBPK) model to simulate the plasma concentration and 13CO2 exhalation after [2-13C]uracil administration to DPD-suppressed dogs was developed. Simulation using this PBPK model should be useful in clinical situations where DPD-deficient patients at risk are to be detected with [2-13C]uracil as an in vivo probe.

Calcium [13C]carbonate breath test for quantitative measurement of total gastric acid in rats

Abstract Objective. A traditional measurement of gastric acid, involving nasogastric intubation of stomach and acid suction, has been suggested as a gold standard. However, this causes the patient discomfort and cost increase, and is ‘time-consuming’. Material and methods. A calcium [13C]carbonate (Ca13CO3) breath test was carried out in rats without or with concomitant drugs omeprazole (OMP) and pentagastrin (PG) known as an inhibitor and an inducer of acid, respectively. This test was aimed at evaluating a correlation between the breath response and the total amount of gastric acid. To search for an absorption pathway of 13CO2 gas produced by the reaction of Ca13CO3 with hydrochloric acid in the stomach of rats, we compared the breath responses after intra-gastric administration of 13CO2 gas and sodium [13C]bicarbonate (NaH13CO3). Results. A linear relationship of the breath parameter (breath-Cmax) with the dose of Ca13CO3 was obtained in the range of 4–200 µmol/kg. However, theses parameters were saturated at >200 µmol/kg. The direct correlation between the breath-Cmax and the total amount of gastric acid in rats with or without OMPs or PG (r = 0.994) demonstrated that the change in breath response is an accurate or sensitive indicator of the total amount of gastric acid. 13CO2 gas generated in the rat stomach was likely to diffuse across the stomach wall as 13CO2 gas directly into the blood plasma. Conclusions. The present study showed that Ca13CO3 breath test is a good tool to accurately predict the total amount of gastric acid.

Desirable pharmacokinetic properties of 13C-uracil as a breath test probe of gastric emptying in comparison with 13C-acetate and 13C-octanoate in rats

Objective. To investigate the possible use of a 13C-uracil breath test for gastric emptying by evaluating the pharmacokinetic properties of 13C-uracil in a breath test in rats, in comparison with 13C-acetate and 13C-octanoate, traditional 13C-probes for gastric emptying. Material and methods. Absorption of the 13C-probes from different parts of the gastrointestinal tract was evaluated in fasted rats. 13C-Uracil breath tests for gastric emptying were carried out in conditions where delayed gastric emptying was induced by clonidine, quinpirole, and propantheline, and in a postoperative ileus model. Following oral administration, we measured residual 13C-uracil in the stomach and correlated the amount with the breath response. Results. All the 13C-probes employed were well absorbed from the intestine after intraduodenal administration. After intragastric administration, 13C-uracil was not absorbed from the stomach, but 13C-acetate and 13C-octanoate were partly absorbed from the stomach. The cumulative 14C-uracil recovery (%) at 168 h was 92.3, 6.3, or 0.5%, from expired gases, urine, and feces, respectively. Δ13C values in 13C-uracil breath tests were decreased in conditions characterized by delayed gastric emptying. A highly negative correlation was observed between the breath response and the residual ratio of 13C-uracil in the stomach after oral administration of 13C-uracil, indicating that 13C-uracil can be used as an in vivo probe for evaluating gastric emptying in a quantitative manner. Conclusions. This study showed that 13C-uracil has desirable pharmacokinetic properties as an in vivo probe of gastric emptying. It is thus suggested that the 13C-uracil breath test may be useful for the measurement of gastric emptying in humans.