Theophylline elimination in congestive heart failure

Kuntz, Hans-Dieter; Straub, Heather; May, B.

doi:10.1007/bf01496473

Cited by 24 publications

(20 citation statements)

References 10 publications

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“…Chronic congestive heart failure is followed by haemostasis of the liver due to the development of pressure atrophy of hepatic tissue. [102,108] By an analogous mechanism, cor pulmonale is responsible for reduced plasma clearance of theophylline. [108] Similarly, acute left ventricular failure causes ischaemia of the liver because it causes hypoxia in liver.…”

Section: Concomitant Diseasesmentioning

confidence: 99%

Influence of Endogenous and Exogenous Effectors on the Pharmacokinetics of Theophylline

Tröger

Meyer

1995

Clinical Pharmacokinetics

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Theophylline has been widely used as a bronchodilatory drug for the treatment of neonatal apnoea in premature newborns and patients with obstructive airways disease. The development of analytical equipment and procedures to determine the systemic concentration of theophylline renders it possible to improve the effectiveness of theophylline therapy and reduce the incidence of toxic and adverse effects. Since the beginning of the 1970s, endogenous and exogenous factors (e.g. age, blood pH, concomitant diseases and drug therapy, meal preparation procedure, nutritional habits, pregnancy, gender, smoking and, to a lesser extent, biorhythms), influencing nearly all parameters of theophylline pharmacokinetics have been described. Drug absorption depends on galenic formulation, drug delivery, nutritional habits and the chemical derivatives used. The mean plasma protein binding rates depend on the method of plasma protein determination: acidic blood pH values and advanced age may result in reduced plasma proteins. The volume of distribution depends primarily on age; it is 2-fold greater in newborns than in adults. Furthermore, changes in blood pH values, the plasma protein content and the administration of concomitant drugs may vary this parameter. Biotransformation is the most clinically important pharmacokinetic parameter. Hepatic metabolism accounts for 90% of the metabolism of theophylline. Essentially, 2 microsomal isoenzymes of the cytochrome P450 system appear to be responsible for the N-methylation and 8-hydroxylation of the drug. Age and concomitant disease are the major endogenous effectors influencing biotransformation of theophylline, whereas biorhythms, gender and pregnancy are of lesser importance. Exogenous factors, such as concomitantly administered drugs, smoking and nutritional factors, affect biotransformation by inducing or inhibiting the metabolising enzymes. Because of intra- and interindividual variability in the pharmacokinetics of theophylline, which may be increased by the presence of endogenous and/or exogenous effectors, it is necessary to supervise theophylline therapy by therapeutic drug monitoring if target concentrations are to be achieved.

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Section: Concomitant Diseasesmentioning

confidence: 99%

Influence of Endogenous and Exogenous Effectors on the Pharmacokinetics of Theophylline

Tröger

Meyer

1995

Clinical Pharmacokinetics

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“…On the other hand, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP3A5*3, UGT2B7*2, UGT2B7*3, and the C3435T mutation of MDR1 did not affect the pharmacokinetics of R-and S-carvedilol in healthy Japanese. 2,6) Several pharmacokinetic studies have suggested that hepatic elimination of certain drugs via oxidative metabolism is impaired in patients with heart failure (HF) [7][8][9][10][11][12][13] ; that is, the CL/F value of prazosin after oral administration in HF patients was 46% of that in healthy subjects. 7) It was also reported that the CL/F value of aminopyrine after oral administration in HF patients in the aminopyrine breath test was 24% of that in control subjects.…”

mentioning

confidence: 99%

“…9,10) The CL value of theophylline (CYP1A2 substrate) after intravenous administration was markedly decreased in HF patients. 11,12) Recently, population pharmacokinetic analysis has revealed that the CL/F value of mexiletine, which is mainly metabolized by CYP1A2 and CYP2D6, is reduced significantly in HF patients as compared with non-HF patients. 13) However, it is still unclear whether the pharmacokinetics of R-and/or S-carvedilol is altered by HF.…”

mentioning

confidence: 99%

Pharmacokinetics of R- and S-Carvedilol in Routinely Treated Japanese Patients with Heart Failure

Horiuchi

Nozawa

Fujii

et al. 2008

Biological & Pharmaceutical Bulletin

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Carvedilol is a b-adrenoceptor antagonist, clinically used to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmias.1) Orally administered carvedilol undergoes stereoselective first-pass metabolism, and the maximal plasma concentration of R-enantiomer with low b-blocking activity is approximately 2-fold higher than that of S-enantiomer with high b-blocking activity.2) Carvedilol is metabolized extensively via aliphatic sidechain oxidation, aromatic ring oxidation, and conjugation pathways.3) Oldham and Clarke 4) reported that oxidative activity for carvedilol is observed in cytochrome P450 (CYP) 2D6, 2C9, 3A4, and 1A2. In addition, Ohno et al. 5) reported that UDP-glucuronosyltransferase (UGT) 2B7, 2B4, and 1A1 are capable of catalyzing the glucuronidation of carvedilol. In the previous study, we examined the effect of CYP2D6*10, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP3A5*3, UGT2B7*2, UGT2B7*3, and the C3435T mutation of MDR1 on the pharmacokinetics of carvedilol in 54 Japanese volunteers. 2,6) The oral clearance (CL/F) and also volume of distribution (V/F) of R-and S-carvedilol were significantly lower in subjects with the CYP2D6*10 allele than those with CYP2D6*1/*1, *1/*2, or *2/*2 genotype, indicating that the systemic clearance (CL) and/or bioavailability (F) of both enantiomers is significantly altered in Japanese with the CYP2D6*10 allele. On the other hand, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP3A5*3, UGT2B7*2, UGT2B7*3, and the C3435T mutation of MDR1 did not affect the pharmacokinetics of R-and S-carvedilol in healthy Japanese. 2,6) Several pharmacokinetic studies have suggested that hepatic elimination of certain drugs via oxidative metabolism is impaired in patients with heart failure (HF) [7][8][9][10][11][12][13] ; that is, the CL/F value of prazosin after oral administration in HF patients was 46% of that in healthy subjects.7) It was also reported that the CL/F value of aminopyrine after oral administration in HF patients in the aminopyrine breath test was 24% of that in control subjects. 8) In addition, CL values of midazolam and quinidine (CYP3A4 substrates) after intravenous administration were decreased by 32% and 33% in HF patients, respectively. 9,10) The CL value of theophylline (CYP1A2 substrate) after intravenous administration was markedly decreased in HF patients. 11,12) Recently, population pharmacokinetic analysis has revealed that the CL/F value of mexiletine, which is mainly metabolized by CYP1A2 and CYP2D6, is reduced significantly in HF patients as compared with non-HF patients.13) However, it is still unclear whether the pharmacokinetics of R-and/or S-carvedilol is altered by HF. In the present study, therefore, we investigated the pharmacokinetics of R-and S-carvedilol in routinely treated Japanese patients with HF. MATERIALS AND METHODS Subjects and Study ProtocolTwenty-four Japanese patients with HF (16 men and 8 women) participated in this study. Their age was between 45 and 91 years old (70.5Ϯ11.3 years), and their body weight was between 36...

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“…In 50 patients with chronic congestive HF (grade III/IV), given 208 mg IV of theophylline, Kuntz et al [162] found a greatly reduced clearance and a corresponding prolongation of half-life (25.7 ml/kg/hr and 5.7 hours, respectively, vs. 68.3 ml/kg/hr and 3.1 hours in controls). The main factor responsible for the altered metabolism of theophylline was the impairment of hepatic function due to heart failure, as evidenced by a decreased galactose elimination capacity.…”

Section: Other Agents Theophyllinementioning

confidence: 99%

Effects of cardiovascular disease on pharmacokinetics

Rodighiero

1989

Cardiovasc Drug Ther

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The pathophysiologic changes occurring in cardiovascular disease can affect the kinetics of drugs in several different ways. The present review examines these modifications and the underlying mechanisms. The kinetics of specific agents, such as antiarrhythmic, antihypertensive, cardiotonic, and other drugs are considered, and the clinical implications are outlined. The clinician should be aware of these modifications, because they require an adjustment of the dosage regimen. A rational basis for a correct therapeutic choice can be provided by adequate knowledge of these modifications.

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Theophylline elimination in congestive heart failure

Cited by 24 publications

References 10 publications

Influence of Endogenous and Exogenous Effectors on the Pharmacokinetics of Theophylline

Influence of Endogenous and Exogenous Effectors on the Pharmacokinetics of Theophylline

Pharmacokinetics of R- and S-Carvedilol in Routinely Treated Japanese Patients with Heart Failure

Effects of cardiovascular disease on pharmacokinetics

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