Clinical Importance of Hepatic Cytochrome P450 in Drug Metabolism

Spatzenegger, Margit; Jaeger, Walter

doi:10.3109/03602539508998329

Cited by 219 publications

(115 citation statements)

References 85 publications

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“…Because our inhibition and recombinant experiments do not support a significant role of CYP1A2 in benidipine metabolism, the observed significant correlation between benidipine metabolism and CYP1A2 is probably derived from the significant correlation between the activity of CYP1A2 and CYP3A (Pearson r ϭ 0.57; p ϭ 0.02) in the bank of human livers tested. It is interesting that the two major metabolic pathways of benidipine are catalyzed by the same CYP3A subfamily despite their different metabolic mechanisms, but this may be explained by the fact that CYP3A has a broad substrate specificity (Spatzenegger and Jaeger, 1995;Patki et al, 2003). Taken together, these results suggest that CYP3A is the major enzyme involved in the metabolism of benidipine at concentrations in the usual experimental ranges.…”

Section: Yoon Et Alsupporting

confidence: 48%

Characterization of Benidipine and Its Enantiomers' Metabolism by Human Liver Cytochrome P450 Enzymes

Yoon¹,

Kim²,

Kim³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Benidipine is a dihydropyridine calcium antagonist that has been used clinically as an antihypertensive and antianginal agent. It is used clinically as a racemate, containing the (؊)-␣ and (؉)-␣ isomers of benidipine. This study was performed to elucidate the metabolism of benidipine and its enantiomers in human liver microsomes (HLMs) and to characterize the cytochrome P450 (P450) enzymes that are involved in the metabolism of benidipine. Human liver microsomal incubation of benidipine in the presence of NADPH resulted in the formation of two metabolites, N-desbenzylbenidipine and dehydrobenidipine. The intrinsic clearance (CL int ) of the formation of N-desbenzylbenidipine and dehydrobenidipine metabolites from (؊)-␣ isomer was similar to those from the (؉)-␣ isomer (1.9 ؎ 0.1 versus 2.3 ؎ 2.3 l/min/pmol P450 and 0.5 ؎ 0.2 versus 0.6 ؎ 0.6 l/min/pmol P450, respectively). Correlation analysis between the known P450 enzyme activities and the rate of the formation of benidipine metabolites in the 15 HLMs showed that benidipine metabolism is correlated with CYP3A activity. The P450 isoform-selective inhibition study in liver microsomes and the incubation study of cDNA-expressed enzymes also showed that the N-debenzylation and dehydrogenation of benidipine are mainly mediated by CYP3A4 and CYP3A5. The total CL int values of CYP3A4-mediated metabolite formation from (؊)-␣ isomer were similar to those from (؉)-␣ isomer (17.7 versus 14.4 l/min/pmol P450, respectively). The total CL int values of CYP3A5-mediated metabolite formation from (؊)-␣ isomer were also similar to those from (؉)-␣ isomer (8.3 versus 11.0 l/min/pmol P450, respectively). These findings suggest that CYP3A4 and CYP3A5 isoforms are major enzymes contributing to the disposition of benidipine, but stereoselective disposition of benidipine in vivo may be influenced not by stereoselective metabolism but by other factors.Benidipine is a highly potent dihydropyridine calcium antagonist that is used clinically as a racemate. This agent shows slow onset and long-lasting antihypertensive and antianginal effects owing to the blockade of calcium ion entry to smooth muscle Yamada et al., 1990). It is currently in clinical use for the treatment of hypertension as a single daily medication (2-8 mg). Like other dihydropyridine calcium antagonists (except nifedipine and mepirodipine), benidipine has asymmetric carbons both in the 1,4-dihydropyridine ring and in the side chain of the benzylpiperidine ring. This drug is a racemate consisting of two optical isomers [(ϩ)-␣ and (Ϫ)-␣ isomer] of the four possible optical isomers because the other isomers are removed during the crystallization step on synthesis (Kobayashi and Kobayashi, 1998). The (ϩ)-␣ isomer was 30-to 100-fold more active than the (Ϫ)-␣ isomer in terms of the antihypertensive effect after i.v. administration to the spontaneously hypertensive rat (Muto et al., 1988).Pharmacokinetic studies in rats (Kobayashi and Kobayashi, 1998) and humans (Kobayashi et al., 1997) have shown that benidipine is we...

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Section: Yoon Et Alsupporting

confidence: 48%

Characterization of Benidipine and Its Enantiomers' Metabolism by Human Liver Cytochrome P450 Enzymes

Yoon¹,

Kim²,

Kim³

et al. 2007

Drug Metab Dispos

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“…CYP3A4 accounts for 28% of the total amount of CYP within the human liver, and is involved in the metabolism of 60% of medications. 4) Gene expression in PBL is controversial; CYP3A5 but not CYP3A4 is selectively expressed in human PBL. 19) CYP3A4 gene expression in human PBL was measured by RT-PCR from 2 mg of total RNA.…”

Section: Discussionmentioning

confidence: 99%

“…Studies on such alterations generally require systemic administration of a drug or probe substance and the application of standard pharmacokinetic approaches. 4,5) Although small amounts of needle biopsy material from the liver can be used for assessment of gene expression, the process of biopsy is accompanied by practical and ethical problems. Some CYPs are also expressed in extra-hepatic tissues such as the lung, the kidney and the small intestine.…”

mentioning

confidence: 99%

Cytochrome P450 gene expression levels in peripheral blood mononuclear cells in comparison with the liver

et al. 2004

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Cytochromes P450 (CYPs) compose a superfamily of similar proteins involved in detoxification and elimination, as well as activation of a wide variety of compounds. Most CYP family members are localized in the liver. In order to assess whether peripheral blood leukocytes (PBL) are available as a surrogate for the determination of CYP gene expression levels in the liver, we compared CYP gene expression levels in PBL with those in liver tissues from patients with hepatocellular carcinoma (HCC). We measured CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 2F1, 2J2, 3A4, 3A5, etabolism of foreign compounds in the body to polar, hydrophilic metabolites is an important prerequisite for detoxification and elimination of xenobiotics from the body. The cytochromes P450 (CYPs) are a superfamily of similar heme-containing proteins that are involved in the oxidative metabolism of xenobiotics. CYPs also catalyze the bioactivation and inactivation of a wide variety of endogenous compounds, including steroid hormones and eicosanoids. Most of the CYP family members are located in the liver.1-3) Many environmental factors, stress, drugs and diseases influence the expression levels of CYP family members, which may lead to alterations of hepatic drug metabolism in man. Studies on such alterations generally require systemic administration of a drug or probe substance and the application of standard pharmacokinetic approaches. 4,5) Although small amounts of needle biopsy material from the liver can be used for assessment of gene expression, the process of biopsy is accompanied by practical and ethical problems. Some CYPs are also expressed in extra-hepatic tissues such as the lung, the kidney and the small intestine. Although xenobiotics are transported via the blood and peripheral blood is obtained for routine medical examination, little is known about CYP expression in peripheral blood cells. So far, CYP1A1, 1B1, 2D6, 2E1 and 3A genes have been shown to be expressed in peripheral blood.6, 7) In order to determine whether peripheral blood leukocytes (PBL) are applicable as a surrogate for assessment of CYP gene expression in the liver, we measured CYP gene expression levels in PBL and the liver, and studied the intra-individual correlation between them. Approximately 70% of human liver CYPs is accounted for by CYP1A2, 2A6, B6, 2C, 2D6, 2E1 and 3A.8) Here, we measured the expression levels of 19 CYP genes, i.e., CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 2F1, 2J2, 3A4, 3A5, 3A7, 4A11, 4B1 and CYP27, by real-time reverse-transcription (RT)-PCR. Furthermore, we compared the CYP gene expression levels in tumor and non-tumor tissues from liver cancers to assess whether carcinogenesis is associated with specific changes in CYP gene expression levels or not. Materials and MethodsWe investigated 18 patients with hepatocellular carcinoma (HCC), 2 patients with intrahepatic cholangiocarcinoma (ICC), 2 with bile duct cancer (BDK) and 1 with colon cancer metastasized to the liver (META) who underwent surgical r...

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“…A number of AEDs and nonAEDs are able to induce or inhibit the CYP isoenzymes, a process that is dose dependent and may involve different CYP isoenzymes. Of the ∼25 different isoenzymes of CYP that have been identified, eight are known to be involved in the metabolism of AEDs (Table 1), and three are considered to be of particular importance in AED interactions: CYP2C9, CYP2C19, and CYP3A4 (5,14,15). CYP3A4, in particular, is susceptible to induction and inhibition by many compounds, and CBZ is capable of inducing its own metabolism (autoinduction) via this isoenzyme.…”

Section: Pharmacokinetic Interactionsmentioning

confidence: 99%

The Importance of Drug Interactions in Epilepsy Therapy

et al. 2002

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Summary: Long-term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme-inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)].The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZepoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non-AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.

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Clinical Importance of Hepatic Cytochrome P450 in Drug Metabolism

Cited by 219 publications

References 85 publications

Characterization of Benidipine and Its Enantiomers' Metabolism by Human Liver Cytochrome P450 Enzymes

Characterization of Benidipine and Its Enantiomers' Metabolism by Human Liver Cytochrome P450 Enzymes

Cytochrome P450 gene expression levels in peripheral blood mononuclear cells in comparison with the liver

The Importance of Drug Interactions in Epilepsy Therapy

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