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1.
Drug Metab Pharmacokinet ; 26(3): 300-6, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21383522

ABSTRACT

The oral bioavailability of some drugs is markedly lower in cynomolgus monkeys than in humans. One of the reasons for the low bioavailability in cynomolgus monkeys may be the higher metabolic activity of intestinal CYP3A; however, the species differences in intestinal metabolic activities of other CYP isoforms between cynomolgus monkeys and humans are not well known. In the present study, we investigated the intrinsic clearance (CL(int)) values in pooled intestinal microsomes from cynomolgus monkeys and humans using 25 substrates of human CYP1A2, CYP2J2, CYP2C, and CYP2D6. As in humans, intestinal CL(int) values of human CYP1A2 and CYP2D6 substrates in cynomolgus monkeys were low. On the other hand, intestinal CL(int) values of human CYP2J2 and CYP2C substrates in cynomolgus monkeys were greatly higher than those in humans. Using immunoinhibitory antibodies and chemical inhibitors, we showed that the higher intestinal CL(int) values of the human CYP2J2 and CYP2C substrates in cynomolgus monkeys might be caused by monkey CYP4F and CYP2C subfamily members, respectively. In conclusion, there is a possibility that the greatly higher metabolic activity of CYP2C and CYP4F in cynomolgus monkey intestine is one of the causes of the species difference of intestinal first-pass metabolism between cynomolgus monkeys and humans.


Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Intestines/enzymology , Macaca fascicularis/metabolism , Pharmaceutical Preparations/metabolism , 2-Pyridinylmethylsulfinylbenzimidazoles/metabolism , Amodiaquine/metabolism , Animals , Antibodies/immunology , Antibodies/pharmacology , Astemizole/metabolism , Biocatalysis/drug effects , Cytochrome P-450 CYP1A2/metabolism , Cytochrome P-450 CYP2D6/metabolism , Cytochrome P-450 CYP2J2 , Cytochrome P-450 CYP3A/immunology , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/immunology , Fatty Acids, Unsaturated/pharmacology , Humans , Isoenzymes/metabolism , Lansoprazole , Microsomes/drug effects , Microsomes/enzymology , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Nicardipine/metabolism , Nimodipine/metabolism , Paroxetine/metabolism , Species Specificity , Terfenadine/metabolism
2.
Drug Metab Pharmacokinet ; 25(4): 335-42, 2010.
Article in English | MEDLINE | ID: mdl-20814154

ABSTRACT

Using physiologically-based pharmacokinetic model simulations with the assumption that elimination of inactivator is not altered by mechanism-based inactivation (MBI) of the target enzyme, we examined at what concentrations the influence of MBI could be accurately and simply predicted. The method utilizing maximum unbound systemic concentration as the inactivator concentration (method 1) tended to overestimate this influence, and accuracy expressed as the ratio of estimated and exact fold decrease in enzyme activity ranged from 0.80 to 8.41. In addition, when the volume of distribution was large or the absorption rate constant was small, method 1 provided relatively precise estimation, with the ratio of nearly 1. We propose use of two concentrations, the steady-state average unbound liver concentration and maximum limit of steady-state average unbound liver concentration, to predict the effects of MBI. The accuracy of prediction of MBI using these two concentrations ranged from 0.90 to 1.04 and 0.92 to 2.96, respectively, and was higher than that with method 1. These two concentrations can be obtained early in the drug development process, and estimated results can be expected to contribute to determination of the effects of MBI.


Subject(s)
Cytochrome P-450 Enzyme Inhibitors , Pharmacokinetics , Area Under Curve , Computer Simulation , Drug Interactions , Humans , Liver/metabolism , Models, Biological
3.
Drug Metab Dispos ; 38(11): 1967-75, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20702772

ABSTRACT

To select high bioavailability compounds, it is necessary to predict the first-pass metabolism in the intestine. However, in vitro-in vivo predictions of the intestinal metabolism have proven both challenging and less definitive. The purpose of this study was to investigate prediction of intestinal first-pass metabolism in humans using cynomolgus monkeys. First, we investigated intrinsic metabolic activities in intestinal microsomes of monkeys (MIM) and humans (HIM) (CL(int, MIM) and CL(int, HIM), respectively) of 18 CYP3A substrates. The CL(int, MIM) values were found to be relatively high and showed excellent correlation with the CL(int, HIM) values. Subsequently, we determined the plasma concentrations of 9 CYP3A substrates (buspirone, carbamazepine, diazepam, felodipine, midazolam, nicardipine, nifedipine, saquinavir, and verapamil) in monkeys after an oral dose of 2 mg/kg with or without an oral dose of 5 mg/kg ketoconazole and calculated AUC((+vehicle))/AUC((+ketoconazole)), defined as F(g, monkey(observed)); we confirmed that the dose of ketoconazole inhibited only intestinal CYP3A metabolism by preliminary in vitro and in vivo experiments using ketoconazole. The F(g, monkey(observed)) was lower than the F(g, human(observed)) for most compounds, but moderate correlation was observed. Furthermore, using these data, we established a new methodology to estimate F(g, human(predicted)) more precisely on the basis of the assumption that intestinal physiological conditions other than intrinsic metabolic activity would be the same between monkeys and humans. In conclusion, the in vivo model using cynomolgus monkeys in this study is useful for prediction of intestinal first-pass metabolism by CYP3A in humans because it was able to predict F(g, human) of all nine compounds investigated.


Subject(s)
Cytochrome P-450 CYP3A/metabolism , Intestines/enzymology , Microsomes/enzymology , Pharmaceutical Preparations/blood , Administration, Oral , Animals , Chromatography, Liquid , Cytochrome P-450 CYP3A Inhibitors , Humans , Ketoconazole/pharmacology , Liver/enzymology , Macaca fascicularis , Male , Microsomes, Liver/enzymology , Pharmaceutical Preparations/administration & dosage , Predictive Value of Tests , Species Specificity , Substrate Specificity , Tandem Mass Spectrometry
4.
Article in English | MEDLINE | ID: mdl-12137998

ABSTRACT

A convenient liquid chromatographic-single quadrupole mass spectrometric (LC-MS) method was developed and validated for the determination of chlorpheniramine maleate (INN name: chlorphenamine) in human plasma. The method had advantages of a single liquid-liquid extraction with diethylether and high sensitivity. The linearity was also excellent over the concentration range of 0.52-20.8 ng/ml of chlorpheniramine maleate. The intra- and inter-day precision and accuracy ranged between 0.0 and 13.9%, showing a good reproducibility. This developed method was successfully applied to analysis of chlorpheniramine maleate in clinical studies.


Subject(s)
Chlorpheniramine/blood , Histamine H1 Antagonists/blood , Chromatography, Liquid/methods , Humans , Mass Spectrometry/methods , Reference Standards , Reproducibility of Results , Sensitivity and Specificity
5.
Br J Clin Pharmacol ; 53(3): 296-304, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11874393

ABSTRACT

AIMS: It has been widely recognized that classical antihistamines induce sedation as an adverse effect, while second-generation antihistamines have few if any sedative effects. In order to evaluate the sedative properties of ebastine, a second-generation antihistamine, its effect on cognitive performance in healthy subjects was compared with placebo and (+)-chlorpheniramine. METHODS: Twelve healthy male subjects were instructed to perform six types of attention-demanding cognitive tasks, and objective measurements of reaction times and accuracy was made before and after drug administration. Their sleepiness levels were also monitored. Test drugs were ebastine 10 mg, placebo and two doses of (+)-chlorpheniramine 2 mg and 6 mg, as positive controls. Plasma drug concentrations at the end of the study were analysed. RESULTS: After treatments with (+)-chlorpheniramine, the reaction times of the tasks were significantly prolonged (e.g. ratios of after/before dosing: placebo (0.998 +/- 0.113) vs (+)-chlorpheniramine 2 mg (1.103 +/- 0.083; P<0.05) or (+)-chlorpheniramine 6 mg (1.170 +/- 0.139; P<0.001) in a 7 ms visual discrimination time task) and the accuracy was significantly decreased (e.g. ratios: placebo (1.038 +/- 0.158) vs (+)-chlorpheniramine 2 mg (0.792 +/- 0.202; P<0.01) or (+)-chlorpheniramine 6 mg (0.837 +/- 0.222; P<0.05) in a 7 ms task). On the other hand, performance was not affected by ebastine or placebo treatment (e.g. ebastine 10 mg (reaction time ratio; 1.014 +/- 0.067 and accuracy ratio; 0.990 +/- 0.146) in a 7 ms task). Subjective sleepiness was also not affected by ebastine but (+)-chlorpheniramine significantly increased sedation. With respect to the relationship between plasma drug concentrations and task performance, the latter deteriorated with an increase in plasma (+)-chlorpheniramine concentration (e.g. r=0.439 (P=0.007) in a 5 ms and r = 0.352 (P=0.039) in a 7 ms task), but it did not correlate with the plasma concentration of carebastine, an active metabolite of ebastine. CONCLUSIONS: Ebastine 10 mg did not cause any cognitive impairment or subjective sleepiness. On the other hand, (+)-chlorpheniramine impaired cognitive function and induced sleepiness even at 2 mg, the recommended dose in over-the-counter medication. In addition, impaired CNS performance was significantly correlated with plasma (+)-chlorpheniramine concentration.


Subject(s)
Butyrophenones/adverse effects , Chlorpheniramine/adverse effects , Cognition/drug effects , Histamine H1 Antagonists/adverse effects , Piperidines/adverse effects , Administration, Oral , Adult , Butyrophenones/blood , Chlorpheniramine/blood , Dose-Response Relationship, Drug , Histamine H1 Antagonists/blood , Humans , Male , Piperidines/blood , Reaction Time/drug effects , Sleep/drug effects , Stereoisomerism , Visual Perception/drug effects
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