First-pass metabolism of midazolam by the human intestine*

Paine, Mary F.; Shen, Danny D.; Kunze, Kent L.; Perkins, James D.; Marsh, Christopher L.; McVicar, John P.; Barr, Darlene; Gillies, Bruce S.; Thummel, Kenneth E.

doi:10.1016/s0009-9236(96)90162-9

Cited by 383 publications

(338 citation statements)

References 24 publications

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“…It is known that CYP3A4 is present not only in the liver but also in the small intestine (Watkins 1994). Paine et al (1996) have reported that midazolam undergoes extensive intestinal metabolism and have suggested that this plays a major role in the firstpass metabolism of this drug. Therefore, the differential effects of carbamazepine on the Cmax of midazolam and alprazolam appear to be ascribable to the difference between the two drugs in the extent of first-pass metabolism, especially that in the small intestine.…”

Section: Discussionmentioning

confidence: 99%

Effect of Carbamazepine on the Single Oral Dose Pharmacokinetics of Alprazolam

Furukori

Otani

Yasui

et al. 1998

Neuropsychopharmacology

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The triazolobenzodiazepine alprazolam is used extensively in the treatment of anxiety and panic disorders (Greenblatt and Wright 1993). A significant concentration-effect relationship for alprazolam has been suggested in the treatment of panic disorder; optimal reduction of anxiety occurs in the plasma concentration range of 20-40 ng/ml, whereas the central nervous system (CNS) depressant side effects increase progressively at higher plasma concentrations (Greenblatt and Wright 1993).Alprazolam is metabolized primarily by the hepatic microsomal oxidation, yielding 4-and ␣ -hydroxyalprazolam as its principal metabolites (Greenblatt and Wright 1993). Previous studies have suggested that neither cytochrome P450 (CYP) 2D6 (Bertilsson et al. 1988) nor CYP2C19 (Otani et al. 1997a) is involved in the metabolism of alprazolam. Meanwhile, the in vitro study by von Moltke et al. (1994) has shown that ketoconazole, an inhibitor of CYP3A4 (Olkkola et al. 1994;Watkins 1994), inhibits the 4-and ␣ -hydroxylation of alprazolam, suggesting that alprazolam is metabolized by CYP3A4. Furthermore, Yasui et al. (1996) have reported that erythromycin, an inhibitor of CYP3A4 (Olkkola et al. 1993;Watkins 1994) Carbamazepine has been used increasingly in the treatment of psychiatric disorders (Siris 1993;Post et al. 1994;Otani et al. 1996a). However, it has been suggested that carbamazepine induces the metabolism of several psychotropic drugs (Arana et al. 1986;Backman et al. 1996;Otani et al. 1996b;1997b) by a not fully characterized enzyme induction. Previous studies have suggested that carbamazepine induces CYP3A4 (Wietholtz et al. 1989;Pirmohamed et al. 1994;Yue et al. 1994), but not CYP1A2 (Wietholtz et al. 1989), CYP2D6 (Yue et al. 1994) nor UDP-glucuronosyltransferases (Yue et al. 1994). Therefore, carbamazepine may decrease plasma concentration of alprazolam by inducing its metabolism. In fact, Arana et al. (1988) has reported that carbamazepine decreased plasma concentration of alprazolam in one psychiatric patient. However, there has been no systematic study on the effect of carbamazepine on the plasma concentration and/or metabolism of alprazolam.Therefore, we studied the effect of carbamazepine on the single oral dose pharmacokinetics of alprazolam in healthy volunteers. We also expected that the present study would provide further evidence for the involvement of CYP3A4 in the metabolism of alprazolam. METHODS SubjectsThe subjects were seven healthy male volunteers. The mean Ϯ SD of age was 32.7 Ϯ 6.6 years, and that of body weight was 60.9 Ϯ 4.6 kg. Three subjects were smokers ( Ն 10 cigarettes/day), and the remaining four were nonsmokers. The study protocol was approved by the Ethics Committee of Hirosaki University Hospital, and each subject gave his written informed consent before the study. ProtocolThe study was conducted in a double-blind, randomized crossover manner, with at least a 6-week washout period. The subjects were allocated randomly to one of the two treatment sequences, placebo-carbamazepine or carbamazepin...

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Section: Discussionmentioning

confidence: 99%

Effect of Carbamazepine on the Single Oral Dose Pharmacokinetics of Alprazolam

Furukori

Otani

Yasui

et al. 1998

Neuropsychopharmacology

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“…Equilibrium Dialysis-Equilibrium dialysis experiments were performed in 0.5-ml Plexiglass cells separated by a dialysis membrane (molecular mass cutoff 12-14 kDa) (33,34). 1 M GST (300 l) was dialyzed against an equal volume of 0.5-50 M GS-NBD in a 25°C horizontal shaker water bath.…”

Section: Methodsmentioning

confidence: 99%

The Catalytic Tyr-9 of Glutathione S-Transferase A1-1 Controls the Dynamics of the C terminus

Nieslanik

Atkins

2000

Journal of Biological Chemistry

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The glutathione S-transferase enzymes (GSTs) have a tyrosine or serine residue at their active site that hydrogen bonds to and stabilizes the thiolate anion of glutathione, GS ؊ . The importance of this hydrogen bond is obvious, in light of the enhanced nucleophilicity of GS ؊ versus the protonated thiol. Several A-class GSTs contain a C-terminal segment that undergoes a ligand-dependent local folding reaction. Here, we demonstrate the effects of the Y9F substitution on binding affinity for glutathione conjugates and on rates of the order-disorder transition of the C terminus in rat GST A1-1. The equilibrium binding affinity of the glutathione conjugate, GS-NBD (NBD-Cl, 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole), was decreased from 4.09 M to 0.641 M upon substitution of Tyr-9 with Phe. This result was supported by isothermal titration calorimetry, with K d values of 1.51 M and 0.391 M for wild type and Y9F, respectively. The increase in binding affinity for the mutant is associated with dramatic decreases in rates for the C-terminal order-disorder transition, based on a stopped-flow kinetic analysis. The same effects were observed, qualitatively, for a second GSH conjugate, GSethacrynic acid. Apparently, the phenolic hydroxyl group of Tyr-9 is critical for orchestrating C-terminal dynamics and efficient product release, in addition to its role in lowering the pK a of GSH.The importance of protein dynamics and flexibility to the energetics of ligand binding is well appreciated and has been illustrated in a number of systems (1-5). In many cases, a protein-ligand interaction appears to drive a flexible segment to fold into a rigid, ligand-bound conformation (6, 7). An analogy between global protein folding and ligand binding has been only recently described (8 -11). The concept of folding funnels, where folding progresses via multiple routes rather than a single pathway, can be likened to binding where a ligand drives an ensemble of local states to a single conformation. However, the detailed mechanism of any ligand-dependent, localized folding process remains elusive and is probably less well understood than global folding (12).The glutathione S-transferase (GST) 1 isoform A1-1 provides an outstanding opportunity to dissect the mechanism of a liganddependent local folding reaction. The GSTs are a family of xenobiotic metabolizing enzymes that play a critical role in the detoxication of various endogenous and exogenous compounds. The mammalian cytosolic GSTs consist of seven classes based on sequence similarity and substrate selectivity: ␣ (A), (P), (M), (T), (K), (S), and (Z) (13-17). The catalytic activity of GSTs is based on deprotonation of GSH to form the thiolate (GS Ϫ ), which is a superior nucleophile compared with the protonated thiol. X-ray crystallographic structures and site-directed mutagenesis studies illustrate that each GST contains a conserved tyrosine or serine residue that contributes to thiolate formation through a hydrogen bond (OH⅐⅐⅐⅐ Ϫ SG) and reduces the pK a of bound GSH. Although mutation a...

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“…The CYP3A4-dependent interaction by food-derived agents may be related to the high level expression of CYP3A4 in the small intestine, as well as its broad substrate specificity (Fujita 2004). It has been confirmed that role of intestinal metabolism is significantly greater than hepatic in the firstpass effect for some drugs, e.g., cyclosporine A and midazolam (Isin and Guengerich 2007;Kanazu et al 2005;Kotegawa et al 2002;Paine et al 1996). Even more than half a percent of orally administered cyclosporine A is metabolized by enterocytes (Hebert 1997).…”

Section: Introductionmentioning

confidence: 99%

Age-related changes in the mRNA levels of CYP1A1, CYP2B1/2 and CYP3A1 isoforms in rat small intestine

Pałasz

Wiaderkiewicz

et al. 2011

Genes Nutr

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It has been established beyond doubt that, as well as the liver, the small intestine is an important site of first-pass metabolism of numerous drugs, food components and toxic xenobiotics. However, there is not much information available about age-dependent changes of intestinal biotransformation pathways. In the present paper, we evaluated the relationships between intestinal cytochrome P450 complex activity and the age of animals. The study was carried out on male Sprague-Dawley rats (n = 5) from 5 age series: 0.5-, 2-, 4-, 20-, and 28 months old. Animals at every age series were divided into 4 groups: control and three groups of rats treated with the CYP450 specific inducers: phenobarbital, b-naphtoflavone and dexamethasone, respectively. RNA was isolated from intestinal mucosa, and then standard RT-PCR was used for the analysis of CYP1A1, CYP2B1/2 and CYP3A1 mRNA expression. Additionally, the activities of NADPH-cytochrome P450 and NADH-cytochrome b 5 reductases in the microsomal fraction were biochemically estimated. The constitutive intestinal CYP1A1 mRNA expression changes during maturation and aging. Inducibility of CYP1A1 gene was evident in intestinal mucosa at 2-, 4-and 20-month-old rats. A similar pattern of changes was observed for CYP2B1/2 isoforms. CYP3A1 mRNA expression was not detected in small intestine of 2-week-old rats. In matured rats, constitutive intestinal CYP3A1 expression was low, although after induction, significant increases in CYP3A1 mRNA amount were noted in aged individuals. Intestinal activity of both analyzed reductases was lowest in immature rats and highest in 28-month-old animals. In conclusion, the activity of cytochrome P450 complex in rat small intestine was not decreased by the aging processes, so the high rate of oxidative metabolic reactions in intestinal mucosa can be maintained till the advanced life stage.

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First-pass metabolism of midazolam by the human intestine*

Cited by 383 publications

References 24 publications

Effect of Carbamazepine on the Single Oral Dose Pharmacokinetics of Alprazolam

Effect of Carbamazepine on the Single Oral Dose Pharmacokinetics of Alprazolam

The Catalytic Tyr-9 of Glutathione S-Transferase A1-1 Controls the Dynamics of the C terminus

Age-related changes in the mRNA levels of CYP1A1, CYP2B1/2 and CYP3A1 isoforms in rat small intestine

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