論文

The effects of arterial blood oxygen tension on the pharmacokinetics of theophylline were investigated using an experimental acute hypoxemia model in rats. Conscious rats were exposed to hypoxic gas composed of 8% O2-92% N2. After blood gas tensions and blood pH were stabilized, rats received 5 mg/kg i.v. theophylline, and urine and blood samples were collected. The steady-state volume of distribution, unbound free fraction and hematocrit were unaffected by hypoxemia. Total body clearance was significantly changed (P<.01) from 0.156 ± 0.020 l/kg/hr in control to 0.0556 ± 0.0067 l/kg/hr in hypoxemic rats due to the reduction of both hepatic and renal clearances. In another constant rate i.v. infusion study, the plateau plasma concentration of theophylline was elevated steeply as soon as animals had inspired hypoxic gas, and the elevated concentrations went down after returning to room air. The present results suggested that the variation of arterial oxygen tension is one possible mechanism for a rapid and large intraindividual variability in theophylline clearance in acutely ill patients with chronic obstructive pulmonary disease.

The mean renal epithelial cell residence time, T̄(cell), was defined as a model-independent characteristic of the transcellular transport process in the isolated perfused kidney. The transcellular transport process includes transport at the basolateral membrane, diffusion in the cytosol, and transport at the brush border membrane. The parameter T̄(cell) represents the mean time for the drug secreted from the tubules to pass through the renal epithelial cells, and is calculated as the difference of the mean urinary transit time between secreted drug and inulin in the single-pass perfusion system. Therefore, the urinary excretion rate-time course is indispensable to evaluate T̄(cell). p-Aminohippuric acid was used as a model compound. The bovine erythrocytes in the perfusate kept the isolated kidney in an almost constant physiological condition, including secretion function. The renal vein outflow curves were also analyzed by the use of moments. The dispersion in the cathether was corrected by a deconvolution. The apparent secretion intrinsic clearance and the apparent volume of distribution were calculated from the moments. The present method will be useful for analysis of the transcellular transport mechanism and the effect of disease states on renal transport of drugs.

The in vivo disintegration, dissolution, absorption, and disposition processes of ampicillin products are separated by means of moment analysis. This method is model-independent, that is, any specific model is not assumed. The mean residence time (MRT), mean absorption time (MAT), mean dissolution time (MDT), and mean disintegration time (MDIT) are calculated for several dosage forms of ampicillin. The fraction of dose absorbed (F) is also separated into several fractions corresponding to these in vivo processes. Bioavailability and bioequivalence are discussed in terms of the zero and first moments. The flip-flop behavior of ampicillin is proved by the fact that the MRT following intravenous injection is less than the MAT of any oral dosage form. Absorption of released ampicillin is proved to be a rate-determining step, since the MRT of released ampicillin in the GI tract is the greatest of all MRT corresponding to the in vivo processes. Moment analysis is compared with classical compartment theory, and a new component concept is introduced.

Elimination kinetics of cefmetazole (CMZ) in the rat is studied with changing the dosing amount (D). The normalized area under plasma concentration-time curve (AUC/D) and the mean residence time (MRT) increase with increasing amount of i.v. dose of CMZ. These increases prove the capacity-limited elimination of CMZ without regard to any pharmacokinetic model. The apparent steady-state volume of distribution (Vass) which is defined by D β MRT/AUC is almost independent of D. The simultaneous multi-lines fitting using time course curves following different doses is also attempted to determine the pharmacokinetic model by the application of the minimum AIC estimation (MAICE). AIC, consequently, shows the minimum for the two-compartment model with the Michaelis-Menten elimination. The Yss estimated from this model is about 450 ml/kg which agrees with Vass estimated by moment analysis. © 1982.

Omeprazole is widely used for the treatment of Helicobacter pylori infection. It is metabolized by cytochrome P450 2C19 enzyme (CYP2C19) in the liver. Because this enzyme exhibits a genetic polymorphism, patients with low metabolic activity (poor metabolizers) may be exposed to higher concentrations of this drug than are patients who are extensive metabolizers. Eighty-six patients with cultured H. pylori-positive gastritis or peptic ulcers who completed the treatment and assessment of anti-H. pylori therapy were analyzed for CYP2C19 genotyping using a ploymerase chain reaction-restriction fragment length polymorphism method [the wild-type or two mutant genes (m1 in exon 5 and m2 in exon 4), or both]. Patients were classified into three groups according to the H. pylori eradication regimen: group I (n = 21; omeprazole 40 mg/day and amoxicillin 2000 mg/day for 1 week); group II (n = 21; group I regimen plus sucralfate 4000 mg/day, for 1 week); group III (n = 44; group I regimen plus clarithromycin 800 mg/day, for 1 week). The combination of two mutant alleles (m1/m1, m1/m2, m2/m2-poor metabolizers) was observed in 13 of 86 patients (15), and all poor metabolizer patients achieved H. pylori eradication regardless of their treatment regimens. In addition, the eradication rates of the poor metabolizers were significantly higher than those of other genotypes who carry homozygous or heterozygous normal allele (extensive metabolizers) in group I or groups I and II combined. CYP2C19 genotyping can provide a new strategy to choose an optimal regimen, and this genotyping is especially useful for Japanese, as the frequency of poor metabolizers is five times greater than that found among Caucasians.