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2P-0571 Metabolic fate of pitavastatin - Interaction between fibrates and statins
Tuesday September 30, 2003: Poster Session Therapy 2P-0571
Metabolic fate of pitavastatin - Interaction between fibrates and statins
H. Fujino, S. Shimada, I. Yamada, M. Hirano, Y. Tsunenari, J. Kojima. Tokyo New Drug Research Laboratories I, Kowa Company Ltd., Tokyo, Japan Objective: Recently, cerivastatin was withdrawn from the market due to disproportionate numbers of fatal rhabdomyolysis among patients who had received gemfibrozil concomitantly. To gain a better understanding of the mechanism of drug-drug interaction between fibrates and statins, several experiments in vitro were performed. Results: A remarkable metabolic inhibition of cerivastatin and atorvastatin was noted in the presence of gemfibrozil. However, the increase in unchanged form was fairly small for pitavastatin, compared with other statins. CYP1A2, CYP2C9 and CYP2C19 were shown to be principally responsible for the metabolism of gemfibrozil. However, no metabolism via CYP was observed with fenofibrate, bezafibrate, ciplofibrate and clofibrate. In the presence of gemfibrozil, a focal point was obtained in Dixon plots, demonstrating that there was inhibition of the CYP2C8-, CYP2C9- and CYP3A4-mediated metabolism. Conclusion: The mechanism of the drug-drug interaction was not completely clarified, we propose that the increase in creatine phosphokinase caused by co-administration of gemfibrozil and statins is at least partially due to a CYP-mediated inhibition. 2P-0572
Metabolic fate of pitavastatin - UDP-glucuronosyltransferase involved the lactonization in human and animals
S. Shimada, H. Fujino, I. Yamada, J. Kojima. Kowa Company Ltd., Japan
2P-0573
Metabolic fate of pitavastatin - Interaction between several medicines and statins
T. Saito, H. Fujino, Y. Tsunenari, J. Kojima. Tokyo New Drug Research Laboratories, Kowa Company Ltd., Tokyo, Japan Objective: In general, knowing the metabolic character of medicines can greatly assist in predicting interactions that may be clinically relevant. In the current study, particular focus was concentrated on characterizing drug-drug interaction profiles. To gain a better understanding of drug-drug interaction between various medicines and statins, we performed experiments in vitro using human hepatic microsomes. Results: The metabolic clearance of atorvastatin was about 32 µL/min/mg protein, some 15-fold greater than that of pitavastatin. On co-incubation with several medications, metabolic inhibition of pitavastatin was negligible in human hepatic microsomes. However, a remarkable metabolic inhibition of atorvastatin was noted in the presence of various medicines. The intrinsic clearance of atorvastatin lactone was 20-fold greater than that of its acid form, whereas no marked difference was noted between pitavastatin and its lactone form. Pitavastatin lactone showed no inhibitory effect on CYP3A4-mediated metabolism of testosterone in contrast to atorvastatin lactone. Also, pitavastatin lactone showed no inhibitory effect on CYP2D6-mediated metabolism of debrisoquine.
Conclusions: pitavastatin and its lactone form would be highly unlikely to interact with other drugs in clinical practice. Moreover, our results indicate that future studies assessing the metabolism and drug-drug interactions of statins should include the lactone form. 2P-0574
Atorvastatin effectively increases plasma high-density lipoprotein (HDL) concentrations and lowers HDL-core weight ratio in primary hypercholesterolemics with cholesteryl ester transfer protein-TaqIB B1B1 polymorphism
F. Nishioka 1 , C. Matsubara 1 , D. Yoshihara 1 , T. Hirano 2 , Y. Hiasa 3 , T. Murakami 1 . 1 Department of Medical Chemistry, Faculty of Nutrition, Kagawa Nutrition University, Saitama; 2 First Department of Internal Medicine, Faculty of Medicine, Showa University; 3 Department of Cardiovascular Disease, Tokushima Red Cross Hospital, Japan Primary hypercholesterolemia is the most common genetic dyslipidemia among Japanese myocardial infarction survivors. Lowering of low-density lipoprotein (LDL) is an established effect of atorvastatin, while effects on high-density lipoprotein (HDL) still require evaluation. We compared the ability of atorvastatin to correct plasma lipid and lipoprotein concentrations and HDL subclasses in hypercholesterolemic patients with and without the cholesteryl ester transfer protein (CETP) TaqIB B2 allele. Twenty two hypercholesterolemic subjects with the B2 allele and 22 without it (B1B1 genotype) received atorvastatin (10 mg/day) for 12 weeks. Atorvastatin significantly lowered plasma total and LDL cholesterol by 32% and 40% respectively (P<0.0001, P<0.0001), showing similarity between subjects with and without the TaqIB B2 allele. LDL-core weight ratio (CWR; triglycerides:TG/TG+cholesteryl esters) was significantly increased in subjects with the B2 allele and without it by 19% and 30% respectively (P=0.0387, P=0.0411). High-density lipoprotein (HDL) cholesterol concentrations were increased after atorvastatin treatment by 7%, (P=0.0283) in subjects without the B2 allele, but not in those with the B2 allele. Moreover, the HDL-CWR was decreased in subjects without the B2 allele by 13% (P=0.0407). HDL subfractions were not changed after atorvastatin in both genotypic groups. Irrespective of the B2 allele, atorvastatin significantly decreased CETP masses, but CE transfer rate (CETR) was not decreased in subjects with B2 allele. Preor post-heparin lipoprotein lipase (LPL) or lecithin-cholesterol acyl transferase (LCAT) did not change after atorvastatin in either group. Since atorvastatin did not increase plasma HDL-C in subjects with the B2 allele, this result may be responsible for the drug’s anti-atherogenicity in B2 (+) patients by favoring reverse cholesterol transport. 2P-0575
Metabolic fate of pitavastatin, a new inhibitor of HMG-CoA reductase - Experiments on the carrier-mediated transport systems in liver
S. Shimada 1 , H. Fujino 1 , I. Yamada 1 , M. Moriyasu 2 , J. Kojima 1 . 1 Kowa Company Ltd., Tokyo; 2 Panapharm Laboratories Co., Ltd., Japan Objective: A potent inhibitor of HMG-CoA reductase, pitavastatin has been found to be distributed selectively to liver and excreted in bile unchanged. To understand the mechanism of distribution and excretion, several experiments on the transport of pitavastatin were performed. Results: In the pitavastatin uptake experiments, the cell to medium concentration (C/M) ratio calculated at the equilibrium point after incubation at 37°C was estimated to be 902, indicating that pitavastatin is highly selective of liver. The uptake of pitavastatin in hepatocytes involved carrier-mediated uptake and nonspecific diffusion in the presence of Na+ . There were no practical differences in the kinetic parameters between the presence and absence of Na+ . The metabolic inhibitors and the organic anions reduced the pitavastatin uptake into rat hepatocytes in a concentration-dependent manner. We also investigated the excretion transport systems using mrp2-deficient rats (EHBR) and mdr1a/b knockout mice. No marked difference was observed in the biliary excretion of radioactivity between control rat (SDR) and EHBR after dosing of pitavastatin. Moreover, little radioactive transfer into the brain was detected in the mdr1a/b knockout mouse. Conclusion: Pitavastatin is taken up into the liver by Na+ -independent multispecific anion transporters and ATP-dependent transport systems. However, mrp2 and mdr1-mediated transport mechanisms do not play a major role in the biliary excretion or brain efflux of pitavastatin.
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
TUESDAY
Objective: Pitavastatin is a highly potent inhibitor of HMG-CoA reductase, and is only minimally metabolized in human hepatic microsomes. Lactonization is the major metabolic pathway in humans, and interestingly, the lactone form can be converted to an unchanged form unenzymatically. To clarify the mechanism of lactonization of pitavastatin and the species differences of them, in vitro metabolic reactions were performed. Results: By the addition of UDP-glucuronic acid to hepatic microsomes in humans, pitavastatin lactone was identified as the main metabolite, indicating that pitavastatin lactonization was catalyzed by UDP-glucuronosyltransferase (UGT). Using several human UGT-expressing microsomes, UGT1A3 and UGT2B7 were mainly involved in pitavastatin lactonization. The kinetic studies showed that the metabolic clearance between the acid form and the lactone form of pitavastatin are almost similar in humans. Studies on the in vitro metabolism using hepatic microsomes from rats, dogs, rabbits, monkeys indicated that UGT is responsible for lactonization also in animals. Additionally, remarkable difference of the lactonization by UGT and metabolism of lactone form via CYPs were observed between monkeys and other animals. Conclusion: The mechanism of lactonization was clarified, namely initial glucuronidation by UGT, and then spontaneous lactonization by an elimination reaction of the glucuronide moiety. Moreover, pitavastatin lactonization by UGT was also proceeded in animals, and the species differences in lactonization of pitavastatin were observed.
165
Metabolic fate of pitavastatin - Interaction between fibrates and statins
H. Fujino, S. Shimada, I. Yamada, M. Hirano, Y. Tsunenari, J. Kojima. Tokyo New Drug Research Laboratories I, Kowa Company Ltd., Tokyo, Japan Objective: Recently, cerivastatin was withdrawn from the market due to disproportionate numbers of fatal rhabdomyolysis among patients who had received gemfibrozil concomitantly. To gain a better understanding of the mechanism of drug-drug interaction between fibrates and statins, several experiments in vitro were performed. Results: A remarkable metabolic inhibition of cerivastatin and atorvastatin was noted in the presence of gemfibrozil. However, the increase in unchanged form was fairly small for pitavastatin, compared with other statins. CYP1A2, CYP2C9 and CYP2C19 were shown to be principally responsible for the metabolism of gemfibrozil. However, no metabolism via CYP was observed with fenofibrate, bezafibrate, ciplofibrate and clofibrate. In the presence of gemfibrozil, a focal point was obtained in Dixon plots, demonstrating that there was inhibition of the CYP2C8-, CYP2C9- and CYP3A4-mediated metabolism. Conclusion: The mechanism of the drug-drug interaction was not completely clarified, we propose that the increase in creatine phosphokinase caused by co-administration of gemfibrozil and statins is at least partially due to a CYP-mediated inhibition. 2P-0572
Metabolic fate of pitavastatin - UDP-glucuronosyltransferase involved the lactonization in human and animals
S. Shimada, H. Fujino, I. Yamada, J. Kojima. Kowa Company Ltd., Japan
2P-0573
Metabolic fate of pitavastatin - Interaction between several medicines and statins
T. Saito, H. Fujino, Y. Tsunenari, J. Kojima. Tokyo New Drug Research Laboratories, Kowa Company Ltd., Tokyo, Japan Objective: In general, knowing the metabolic character of medicines can greatly assist in predicting interactions that may be clinically relevant. In the current study, particular focus was concentrated on characterizing drug-drug interaction profiles. To gain a better understanding of drug-drug interaction between various medicines and statins, we performed experiments in vitro using human hepatic microsomes. Results: The metabolic clearance of atorvastatin was about 32 µL/min/mg protein, some 15-fold greater than that of pitavastatin. On co-incubation with several medications, metabolic inhibition of pitavastatin was negligible in human hepatic microsomes. However, a remarkable metabolic inhibition of atorvastatin was noted in the presence of various medicines. The intrinsic clearance of atorvastatin lactone was 20-fold greater than that of its acid form, whereas no marked difference was noted between pitavastatin and its lactone form. Pitavastatin lactone showed no inhibitory effect on CYP3A4-mediated metabolism of testosterone in contrast to atorvastatin lactone. Also, pitavastatin lactone showed no inhibitory effect on CYP2D6-mediated metabolism of debrisoquine.
Conclusions: pitavastatin and its lactone form would be highly unlikely to interact with other drugs in clinical practice. Moreover, our results indicate that future studies assessing the metabolism and drug-drug interactions of statins should include the lactone form. 2P-0574
Atorvastatin effectively increases plasma high-density lipoprotein (HDL) concentrations and lowers HDL-core weight ratio in primary hypercholesterolemics with cholesteryl ester transfer protein-TaqIB B1B1 polymorphism
F. Nishioka 1 , C. Matsubara 1 , D. Yoshihara 1 , T. Hirano 2 , Y. Hiasa 3 , T. Murakami 1 . 1 Department of Medical Chemistry, Faculty of Nutrition, Kagawa Nutrition University, Saitama; 2 First Department of Internal Medicine, Faculty of Medicine, Showa University; 3 Department of Cardiovascular Disease, Tokushima Red Cross Hospital, Japan Primary hypercholesterolemia is the most common genetic dyslipidemia among Japanese myocardial infarction survivors. Lowering of low-density lipoprotein (LDL) is an established effect of atorvastatin, while effects on high-density lipoprotein (HDL) still require evaluation. We compared the ability of atorvastatin to correct plasma lipid and lipoprotein concentrations and HDL subclasses in hypercholesterolemic patients with and without the cholesteryl ester transfer protein (CETP) TaqIB B2 allele. Twenty two hypercholesterolemic subjects with the B2 allele and 22 without it (B1B1 genotype) received atorvastatin (10 mg/day) for 12 weeks. Atorvastatin significantly lowered plasma total and LDL cholesterol by 32% and 40% respectively (P<0.0001, P<0.0001), showing similarity between subjects with and without the TaqIB B2 allele. LDL-core weight ratio (CWR; triglycerides:TG/TG+cholesteryl esters) was significantly increased in subjects with the B2 allele and without it by 19% and 30% respectively (P=0.0387, P=0.0411). High-density lipoprotein (HDL) cholesterol concentrations were increased after atorvastatin treatment by 7%, (P=0.0283) in subjects without the B2 allele, but not in those with the B2 allele. Moreover, the HDL-CWR was decreased in subjects without the B2 allele by 13% (P=0.0407). HDL subfractions were not changed after atorvastatin in both genotypic groups. Irrespective of the B2 allele, atorvastatin significantly decreased CETP masses, but CE transfer rate (CETR) was not decreased in subjects with B2 allele. Preor post-heparin lipoprotein lipase (LPL) or lecithin-cholesterol acyl transferase (LCAT) did not change after atorvastatin in either group. Since atorvastatin did not increase plasma HDL-C in subjects with the B2 allele, this result may be responsible for the drug’s anti-atherogenicity in B2 (+) patients by favoring reverse cholesterol transport. 2P-0575
Metabolic fate of pitavastatin, a new inhibitor of HMG-CoA reductase - Experiments on the carrier-mediated transport systems in liver
S. Shimada 1 , H. Fujino 1 , I. Yamada 1 , M. Moriyasu 2 , J. Kojima 1 . 1 Kowa Company Ltd., Tokyo; 2 Panapharm Laboratories Co., Ltd., Japan Objective: A potent inhibitor of HMG-CoA reductase, pitavastatin has been found to be distributed selectively to liver and excreted in bile unchanged. To understand the mechanism of distribution and excretion, several experiments on the transport of pitavastatin were performed. Results: In the pitavastatin uptake experiments, the cell to medium concentration (C/M) ratio calculated at the equilibrium point after incubation at 37°C was estimated to be 902, indicating that pitavastatin is highly selective of liver. The uptake of pitavastatin in hepatocytes involved carrier-mediated uptake and nonspecific diffusion in the presence of Na+ . There were no practical differences in the kinetic parameters between the presence and absence of Na+ . The metabolic inhibitors and the organic anions reduced the pitavastatin uptake into rat hepatocytes in a concentration-dependent manner. We also investigated the excretion transport systems using mrp2-deficient rats (EHBR) and mdr1a/b knockout mice. No marked difference was observed in the biliary excretion of radioactivity between control rat (SDR) and EHBR after dosing of pitavastatin. Moreover, little radioactive transfer into the brain was detected in the mdr1a/b knockout mouse. Conclusion: Pitavastatin is taken up into the liver by Na+ -independent multispecific anion transporters and ATP-dependent transport systems. However, mrp2 and mdr1-mediated transport mechanisms do not play a major role in the biliary excretion or brain efflux of pitavastatin.
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
TUESDAY
Objective: Pitavastatin is a highly potent inhibitor of HMG-CoA reductase, and is only minimally metabolized in human hepatic microsomes. Lactonization is the major metabolic pathway in humans, and interestingly, the lactone form can be converted to an unchanged form unenzymatically. To clarify the mechanism of lactonization of pitavastatin and the species differences of them, in vitro metabolic reactions were performed. Results: By the addition of UDP-glucuronic acid to hepatic microsomes in humans, pitavastatin lactone was identified as the main metabolite, indicating that pitavastatin lactonization was catalyzed by UDP-glucuronosyltransferase (UGT). Using several human UGT-expressing microsomes, UGT1A3 and UGT2B7 were mainly involved in pitavastatin lactonization. The kinetic studies showed that the metabolic clearance between the acid form and the lactone form of pitavastatin are almost similar in humans. Studies on the in vitro metabolism using hepatic microsomes from rats, dogs, rabbits, monkeys indicated that UGT is responsible for lactonization also in animals. Additionally, remarkable difference of the lactonization by UGT and metabolism of lactone form via CYPs were observed between monkeys and other animals. Conclusion: The mechanism of lactonization was clarified, namely initial glucuronidation by UGT, and then spontaneous lactonization by an elimination reaction of the glucuronide moiety. Moreover, pitavastatin lactonization by UGT was also proceeded in animals, and the species differences in lactonization of pitavastatin were observed.
165