Potential of Lansoprazole as a Novel Probe for Cytochrome P450 3A Activity by Measuring Lansoprazole Sulfone in Human Liver Microsomes

Abstract

Cytochrome P450 (CYP) 3A is the primary CYP isoenzyme subfamily responsible for phase I metabolism of Ͼ50% of drug doses administered to humans.1,2) CYP3A4 is the most prominent CYP in humans, comprising about 30% and 70% of total CYP in the liver and intestine, respectively. CYP3A has very broad substrate specificity, encompassing a wide variety of therapeutic agents.3) Many cancer chemotherapeutic agents such as vinca alkaloids, paclitaxel, irinotecan hydrochloride and other widely used drugs such as amiodarone, diltiazem, lovastatin, erythromycin, and midazolam are substrates for CYP3A. [4][5][6][7] Recently, individual variations in CYP3A activity in the human liver have been reported. 8)Because the pharmacokinetics of various drugs is influenced by individual variations in CYP3A activity, it is important to evaluate those variations in the clinical setting to achieve the optimum therapeutic outcomes. 9)Probe drugs including midazolam, erythromycin, nifedipine, lidocaine, and dextromethorphan and endogenous compounds such as cortisol and testosterone have been utilized to evaluate CYP3A activity.10,11) Watkins 12) proposed three specific CYP3A probes: erythromycin; midazolam; and cortisol. However, the probe drugs available for accurate, safe, and easy measurement of CYP3A activity remain limited.Lansoprazolebenzimidazole, is a proton-pump inhibitor (PPI) that suppresses gastric acid secretion by inhibiting (H ϩ /K ϩ )-ATPase and is prescribed commonly for the treatment of gastric ulcer, reflux esophagitis, etc., with few serious side effects reported. Following administration, lansoprazole is extensively metabolized to 5-hydroxylansoprazole and lansoprazole sulfone (LS) by CYP2C19 and CYP3A, respectively. 13) Masa et al. 14) reported that the metabolism to LS by CYP3A occurs independently of that to 5-hydroxylansoprazole by CYP2C19 in the human liver. Inhibition of one metabolic pathway caused by the genetic polymorphisms of CYPs leads to upregulation of another pathway in vivo. To use lansoprazole as probe drug, these problems should be elucidated in vitro or in vivo. The present study investigated the utility of lansoprazole in assessing CYP3A activity in comparison with previously reported in vitro methods. Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan: and b Research Laboratories, HAB Research Organization; 3rd Floor, Cornea Center Bldg., Ichikawa General Hospital, 5-11-13 Sugano, Ichikawa, Chiba 272-8523, Japan. Received April 13, 2009; accepted May 15, 2009; published online June 1, 2009 Cytochrome P450 (CYP) 3A enzymes are responsible for the metabolism of many drugs. It is useful to know CYP3A activity in individual patients undergoing drug therapy so as to predict the efficacies or adverse events. Lansoprazole is metabolized to Lansoprazole sulfone (LS) by CYP3A, while to 5-hydroxylansoprasole by CYP2C19. The aim of this study was to evaluate whether lansoprazole can be used to assess CYP 3A activity in human liver. Lansoprazole sulfoxidation activity in 14 human liver microsomes was det...

Individual Metabolic Capacity Evaluation of Cytochrome P450 2C19 by Protein and Activity in the Small Intestinal Mucosa of Japanese Pancreatoduodenectomy Patients

“…9,15,16) The microsomes (0.8 mg) were mixed with lansoprazole 10 mM, ethylenediaminetetraacetic acid (EDTA) 0.5 mM, Na-K phosphate 0.33 M, pH 7.4, and distilled water. The reaction was initiated by the addition of an nicotinamide adenine dinucleotide phosphate (NADPH)-generating system (MgCl 2 5 mM, NADP ϩ 0.5 mM, glucose-6-phoshate 5 mM, and 1 unit of glucose-6-phosphate 72 Vol.…”

“…9,16) Several studies have demonstrated that the 5-hydroxylation activity of lansoprazole correlated well with the metabolic activity of the CYP2C19 probe drug mephenytoin. 15,17,18) Our studies have established the value of evaluating the activities of 5-hydroxylation and lansoprazole sulfoxidation as activities of CYP3A4 and CYP2C19 in human liver microsomes and blood samples.…”

“…15,17,18) Our studies have established the value of evaluating the activities of 5-hydroxylation and lansoprazole sulfoxidation as activities of CYP3A4 and CYP2C19 in human liver microsomes and blood samples. 16) We measured the catalysis from lansoprazole to 5-hydroxylansoprazole as a measure of CYP2C19 activity in the small intestinal micro- Anti-rabbit IgG polyclonal antibody was used as a negative control. Details are described in Materials and Methods.…”

Comparison of the Effects of Omeprazole and Rabeprazole on Ticlopidine Metabolism In Vitro

“…All reactions were performed according to the previously reported methods as outlined below (20,21). PHLMs (0.1 -1.0 mg) were mixed with TCL (1.0 -10.0 μM), 0.5 mM EDTA, 100 mM Na-K phosphate buffer (pH 7.4), and distilled water.…”