Nifedipine: Kinetics and hemodynamic effects in patients with liver cirrhosis after intravenous and oral administration

Kleinbloesem, C. H.; Harten, J. Van; Wilson, James P.; Danhof, Meindert; Brummelen, P. Van; Breimer, D. D.

doi:10.1038/clpt.1986.134

Cited by 100 publications

(46 citation statements)

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“…However, others have reported that cirrhosis increases the bioavailability of orally administered CYP3A substrates. 20,22 Cirrhosis produced an increase from 16% to 37% in the bioavailability of isradipine 22 and an increase from 51% to 90% in the bioavailability of nifedipine. 20 However, almost half of the cirrhotic patients in both of these studies had undergone a previous portosystemic shunt surgery.…”

Section: Figmentioning

confidence: 99%

“…20,22 Cirrhosis produced an increase from 16% to 37% in the bioavailability of isradipine 22 and an increase from 51% to 90% in the bioavailability of nifedipine. 20 However, almost half of the cirrhotic patients in both of these studies had undergone a previous portosystemic shunt surgery. When we reanalyzed the published data separately for the effects of cirrhosis and shunting, we found that the F PO of isradipine 22 in patients with portosystemic shunts was 0.46 Ϯ 0.14, and in cirrhotic patients without shunts, this value had dropped to 0.28 Ϯ 0.14.…”

Section: Figmentioning

confidence: 99%

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Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: Effects of transjugular intrahepatic portosystemic shunts

Chalasani

2001

Hepatology

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Transjugular intrahepatic portosystemic shunt (TIPS) is performed to treat some complications of cirrhosis. This study investigated the effects of cirrhosis and TIPS on intestinal and hepatic cytochrome P450 3A (CYP3A) activity. Nine volunteers were cirrhotic patients with TIPS, 9 were cirrhotic controls (matched for sex, age, etiology, and ChildPugh class), and 9 were sex-and age-matched healthy volunteers. Simultaneous doses of midazolam were given intravenously ( The most common primary pathway of drug metabolism is oxidation catalyzed by enzymes in the cytochrome P450 (CYP) superfamily. Enzymes in the CYP3A subfamily are the most abundant CYPs in human liver and metabolize approximately 60% of all drugs that undergo biotransformation. 1 CYP3A substrates are chemically diverse and include alfentanil, cisapride, diltiazem, lovastatin, erythromycin, midazolam, verapamil, triazolam, nifedipine, indinavir, tamoxifen, and cyclosporine. 2 The human CYP3A subfamily consists of at least 3 functional proteins. CYP3A4 is found in all human liver, whereas CYP3A5 is polymorphically expressed and detected in only 10% to 30% of adult liver samples. 3 CYP3A7 is the principal form expressed in fetal tissue. 4 CYP3A4 and 3A5 are generally grouped together and labeled as CYP3A. In addition to the liver, CYP3A enzymes are the most abundant CYPs in the wall of the small intestine and contribute substantially to the first-pass metabolism of orally administered drugs. 5 Rational prescribing of the numerous drugs metabolized by CYP3A enzymes requires a mechanistic understanding of the effect of liver disease on hepatic and intestinal enzyme activity. Midazolam is a selective probe for CYP3A enzyme activity in vivo 6,7 that is not compromised by participation of P-glycoprotein in its elimination. 8 Following oral administration, midazolam is subject to presystemic CYP3A metabolism by both intestinal and hepatic tissues; however, first-pass intestinal metabolism is the major determinant of bioavailability. 6 The simultaneous administration of oral [ 15 N 3 ]midazolam and intravenous midazolam provides the opportunity to measure the independent contributions of the small intestine and the liver to the overall CYP3A activity. 6,7 We used this approach to investigate changes in CYP3A in patients with liver disease.Spontaneous intra-and extrahepatic portosystemic shunts are common in patients with advanced cirrhosis and likely contribute to the altered drug metabolism seen in patients with cirrhosis. Transjugular intrahepatic portosystemic shunt (TIPS) is a side-to-side, nonselective portosystemic shunt that is frequently performed in cirrhotic patients to manage the complications of portal hypertension such as variceal bleeding, ascites, and hepatic hydrothorax. 9,10 Quantifying the disposition of midazolam in these patients provided the opportunity to test the hypothesis that the placement of therapeutic intrahepatic shunts alters hepatic and/or intestinal CYP3A activity. Furthermore, portal vein blood samples, accessed through TIPS, p...

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Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: Effects of transjugular intrahepatic portosystemic shunts

Chalasani

2001

Hepatology

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“…CYP 3A4 can metabolize more than 120 kinds of drugs and participates in 60% of clinical drug metabolisms to different degrees; 40 to 50% of phase I drug metabolisms are performed by CYP 3A4 (McKinnon et al, 1995;Nelson et al, 1996). Patients with liver disease show different degrees of reduced CYP 3A4 expression and weakened CYP 3A4 activity (Huet and Villeneuve, 1983;Kleinbloesem et al, 1986;Lown et al, 1992;Chalasani et al, 2001;Yang et al, 2003;Horiike et al, 2005). GST constitutes one part of the cell's own defenses to block multiple endogenous and environmental toxic compounds, and protects macromolecules from active electron affinity substance attacks (Strange et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Establishment of cytochrome P450 3A4 and glutathione S-transferase A1-transfected human hepatoma cell line and functional analysis

Chang¹,

You²,

Liu³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. This study aimed to enhance the drug metabolism function of the human hepatoma cell line C3A and to explore the related significance for patients with severe liver disease. The important liver phase I and phase II drug metabolism enzymes, cytochrome P450 3A4 (CYP 3A4) and glutathione S-transferase A1 (GST A1), were constructed into a double expression vector and then transfected into C3A cells. Furthermore, in order to increase the expression of CYP 3A4 and GST A1, they were optimized according to human optimal codons. Another double-expression vector, pBudCE4.1-optimized CYP 3A4-optimized GST A1, was constructed and then transfected into C3A to establish a stable cell line. The drug metabolism function of C3A was evaluated. Sequence determination and analysis results showed that the recombinant plasmid pBudCE4.1-CYP 3A4-GST A1 met the application standard and its transfection was successful. The expression and activity of CYP 3A4 and GST A1 in unoptimized C3A cells were higher than those in blank C3A cells. Unoptimized C3A had a better drug metabolism function. Although some C3A cells transfected with pBudCE4.1-optimized CYP 3A4-optimized GST A1 survived, they grew slowly, and were therefore not applicable in clinical practice. Unoptimized C3A is superior to blank C3A in drug metabolism, and could be applied in the bioartificial liver support system as a new material.

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“…[8][9][10][11] Matsuo et al demonstrated that there is a correlation between the CL tot of cyclosporine and the grade severity of liver disease by Child-Pugh classification in patients with hepatitis. 12) However, it is not easy to utilize these approaches to determine the degree of residual hepatic metabolizing ability in patients, as is also the case with creatinine clearance in patients with renal failure.…”

Section: )mentioning

confidence: 99%

mentioning

confidence: 99%

Serum Aminotransferase Activity as a Predictor for Estimation of Total Clearance of Hepatically Metabolized Drugs in Rats with Acute Hepatic Failure

Yokogawa

Ido

Kurihara

et al. 2006

Biological & Pharmaceutical Bulletin

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In treating patients with hepatic failure, it is necessary to set an appropriate drug dosing schedule to take into account of their altered drug disposition kinetics. However, little work has been done to estimate the decrease of total clearance (CL tot ) in relation to the degree of residual hepatic function. Therefore, there is great need for a suitable marker to quantitatively predict the hepatic metabolic capacity in patients with hepatic failure.In humans, there are five predominant families of cytochrome P450 (CYP) species, CYP1A, CYP2C, CYP2D, CYP2E and CYP3A; all of the isoforms differ in their patterns of drug-metabolizing activity, 1) and the amounts of the isoforms in the liver are altered under conditions of hepatic failure.2) The drug-metabolizing activity of the liver may be evaluated on the basis of the correlation between the clearance and the ratio of the metabolite(s) to unchanged drug after the administration of specific inhibitors of various CYP isoforms.Recently, there have been many reports on the expression levels of CYP isoform mRNAs in human liver collected by hepatobiopsy, but no clear correlation has been found between expression levels and the degree of hepatic failure. 3,4) Finnstrom et al. reported that the expression of CYP mRNA in liver is different from that in blood; therefore, blood cannot serve as a surrogate organ for assessment of the expression of the CYP genes in liver.5) Panduro et al. 6) reported that liver regeneration and fibrosis are related to g-carboxylase activity, which is associated with a prolongation of prothrombin time in plasma in rats treated with CCl 4 . Clinically, indocyanine green is commonly used to assess hepatic function. 7)However, none of these procedures appears to be suitable for predicting the decrease in hepatic metabolic activity in patients with hepatic failure.It has been proposed that the drug-metabolizing activity of the liver can be estimated by means of pharmacokinetic analysis after the administration of various probe drugs for CYP isoforms. [8][9][10][11] Matsuo et al. demonstrated that there is a correlation between the CL tot of cyclosporine and the grade severity of liver disease by Child-Pugh classification in patients with hepatitis. 12) However, it is not easy to utilize these approaches to determine the degree of residual hepatic metabolizing ability in patients, as is also the case with creatinine clearance in patients with renal failure.We previously reported that there is a good correlation between mRNA expression and enzyme activity of various CYP isoforms in the livers of rats with acute hepatic failure induced by various doses of CCl 4 . 13) In that study, we also found a good negative correlation between serum aminotransferase activity (AST) and the hepatic activity of each CYP isoform, though the degree of decrease of CL tot varied markedly among CYP isoforms.Here, we present a novel procedure to predict the decrease of CL tot , including that for unknown drugs, based on an increase in serum AST activity in rats with ac...

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Nifedipine: Kinetics and hemodynamic effects in patients with liver cirrhosis after intravenous and oral administration

Cited by 100 publications

References 8 publications

Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: Effects of transjugular intrahepatic portosystemic shunts

Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: Effects of transjugular intrahepatic portosystemic shunts

Establishment of cytochrome P450 3A4 and glutathione S-transferase A1-transfected human hepatoma cell line and functional analysis

Serum Aminotransferase Activity as a Predictor for Estimation of Total Clearance of Hepatically Metabolized Drugs in Rats with Acute Hepatic Failure

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