Multiple-Dose Pharmacokinetics of Pentoxifylline and its Metabolites during Renal Insufficiency

Paap, Christopher M.; Simpson, Karon S; Horton, Michael W.; Schaefer, K; Lassman, Howard B.; Sack, Marshall

doi:10.1177/106002809603000702

Cited by 18 publications

(14 citation statements)

References 5 publications

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“…The same phenomenon has been reported in cirrhotic patients who, after administration of a 400‐mg slow‐release PTX formulation, exhibited a markedly delayed PTX T peak (6.55 vs 2.08 h) and reduced plasma clearance (1.44 vs 3.62 L/h/kg) compared with healthy individuals . By contrast, chronic renal failure, which has no significant effect on PTX elimination, does not modify the T peak of the same 400‐mg sustained‐release preparation …”

Section: Discussionsupporting

confidence: 73%

“…Cirrhotic patients show increased oral bioavailability and reduced plasma clearance of PTX, although the PTX/M1 AUC ratio remains unchanged compared with that of healthy individuals . Conversely, renal dysfunction does not cause accumulation of PTX and M1 but does increase M4 and M5 AUCs and the M4/PTX and M5/PTX AUC ratios . Although no analogous studies have been performed in cardiac patients, pharmacokinetic alterations are expected because reduced cardiac output determines a reduction in perfusion and oxygenation of both liver and kidney, with possible secondary impairment of their metabolic and excretory functions …”

mentioning

confidence: 99%

“…15 Conversely, renal dysfunction does not cause accumulation of PTX and M1 but does increase M4 and M5 AUCs and the M4/PTX and M5/PTX AUC ratios. 16 Although no analogous studies have been performed in cardiac patients, pharmacokinetic alterations are expected because reduced cardiac output determines a reduction in perfusion and oxygenation of both liver and kidney, with possible secondary impairment of their metabolic and excretory functions. 17 The aim of our study was to investigate the time course of plasma concentrations of PTX and its main plasma metabolites (M1, M4, M5) following single 600-mg oral administration of a modified-release formulation in patients with various degrees of cardiac failure and to also investigate whether any demographic or biological variable is correlated with pharmacokinetic changes.…”

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confidence: 99%

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Pharmacokinetics of Pentoxifylline and Its Main Metabolites in Patients With Different Degrees of Heart Failure Following a Single Dose of a Modified‐Release Formulation

Nisi

Panfili

Rosa

et al. 2013

The Journal of Clinical Pharma

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Pentoxifylline (PTX) is extensively metabolized in the body, and all its 3 plasma metabolites (M1, M4, M5) are pharmacologically active. The authors evaluated the pharmacokinetics of PTX and its metabolites in 20 patients with chronic heart failure (CHF). Eleven had moderate and 9 severe CHF. The time courses of PTX, M1, M4, and M5 plasma levels were determined after oral administration of a sustained-release 600-mg tablet of PTX, and for each compound, AUC, maximal plasma concentration (C(max)), and time to C(max) (T(peak)) were calculated. Compared with patients with moderate CHF, those with severe CHF showed a significant delay in T(peak) of PTX (3.9 vs 1.6 hours) and M5 (5.6 vs 3.6 hours), a 59% significant increase in M5 AUC, and a 56% nonsignificant increase in PTX AUC. In the whole population, the AUCs of PTX, M4, and M5 were inversely correlated with markers of liver function, whereas the AUCs of M4 and M5 were inversely correlated with the creatinine clearance. In view of the kinetic features of slow-release formulations (flip-flop phenomenon), the delay in T(peak) of PTX in patients with severe CHF compared with moderate CHF should be ascribed to a reduced elimination rate.

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Section: Discussionsupporting

confidence: 73%

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confidence: 99%

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confidence: 99%

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Pharmacokinetics of Pentoxifylline and Its Main Metabolites in Patients With Different Degrees of Heart Failure Following a Single Dose of a Modified‐Release Formulation

Nisi

Panfili

Rosa

et al. 2013

The Journal of Clinical Pharma

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“…13 Renal insufficiency did not influence the AUC ratios of M1 to pentoxifylline. 26 Thus, the erythrocytes appear to be the main site of the reduction of pentoxifylline to M1. This metabolism in blood has been described previously, [9][10][11] but neither the stereochemistry and kinetics of the reaction nor the conversion of M1 back to pentoxifylline have been investigated.…”

Section: Discussionmentioning

confidence: 99%

Stereoselective metabolism of pentoxifylline in vitro and in vivo in humans

et al. 2002

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Pentoxifylline increases erythrocyte flexibility, reduces blood viscosity, and inhibits platelet aggregation and is thus used in the treatment of peripheral vascular disease. It is transformed into at least seven phase I metabolites, of which two, M1 and M5, are active. The reduction of the keto group of pentoxifylline to a secondary alcohol in M1 takes place chiefly in erythrocytes, is rapidly reversible, and creates a chiral center. The aims of this study were: to develop HPLC methods to separate the enantiomers of M1, to investigate the kinetics of the reversible biotransformation of pentoxifylline to (R)- and (S)-M1 in hemolysed erythrocyte suspension, and to quantify the formation of the enantiomers of M1 (as well as M4 and M5) after intravenous and oral administration of pentoxifylline to human volunteers. (R)- and (S)-M1 could be separated preparatively on a cellobiohydrolase column, while determination in blood or plasma was by HPLC after chiral derivatization with diacetyl-L-tartaric acid anhydride. The metabolism of pentoxifylline to (R)-M1 in suspensions of hemolysed erythrocytes followed simple Michaelis-Menten kinetics (K(m) = 11 mM), while that to (S)-M1 was best described by a two-enzyme model (K(m) = 1.1 and 132 mM). Studies with inhibitors indicated that the enzymes were of the carbonyl reductase type. At a therapeutic blood concentration of pentoxifylline, the calculated rate of formation of (S)-M1 is 15 times higher than that of the (R)-enantiomer. Back-conversion of M1 to pentoxifylline was 3-4 times faster for the (S)- than for the (R)-enantiomer. In vivo, the R:S plasma concentration ratio of M1 ranged from 0.010-0.025 after intravenous infusion of 300 or 600 mg of pentoxifylline, and from 0.019-0.037 after oral administration of 600 mg. The biotransformation of pentoxifylline to M1 was thus highly stereoselective in favor of the (S)-enantiomer both in vitro and in vivo.

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“…Over a period of 4 months, patients of the study group received one pentoxifylline tablet (400 mg) orally once a day (at dinner time), whereas controls received one identical starch tablet on the same schedule. Pentoxifylline dose was selected based on previous pharmacological and clinical studies about the use of this drug in patients with renal impairment [14,15].…”

Section: Methodsmentioning

confidence: 99%

Pentoxifylline decreases serum levels of tumor necrosis factor alpha, interleukin 6 and C-reactive protein in hemodialysis patients: results of a randomized double-blind, controlled clinical trial

González–Espinoza¹,

Rojas–Campos²,

Medina-Pérez³

et al. 2011

Nephrology Dialysis Transplantation

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Aim. The aim of this study was to compare the effect of pentoxifylline versus placebo on serum concentrations of tumor necrosis factor-alpha (TNF-a), interleukin 6 (IL-6) and C-reactive protein (CRP) of hemodialysis (HD) patients. Methods. This is a randomized double-blind, controlled clinical trial. HD patients without infection or drugs with anti-inflammatory effect were randomly allocated to a study (n ¼ 18, pentoxifylline 400 mg/day) or control (n ¼ 18, placebo) group; all patients had arteriovenous fistula. Besides clinical and laboratory monthly assessments, serum TNF-a and IL-6 (ELISA) and CRP (nephelometry) were measured at 0, 2 and 4 months. Conclusions. Pentoxifylline significantly decreased serum concentrations of TNF-a, IL-6 and CRP compared to placebo. Pentoxifylline could be a promising and useful strategy to reduce the systemic inflammation frequently observed in patients on HD.

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Multiple-Dose Pharmacokinetics of Pentoxifylline and its Metabolites during Renal Insufficiency

Cited by 18 publications

References 5 publications

Pharmacokinetics of Pentoxifylline and Its Main Metabolites in Patients With Different Degrees of Heart Failure Following a Single Dose of a Modified‐Release Formulation

Pharmacokinetics of Pentoxifylline and Its Main Metabolites in Patients With Different Degrees of Heart Failure Following a Single Dose of a Modified‐Release Formulation

Stereoselective metabolism of pentoxifylline in vitro and in vivo in humans

Pentoxifylline decreases serum levels of tumor necrosis factor alpha, interleukin 6 and C-reactive protein in hemodialysis patients: results of a randomized double-blind, controlled clinical trial

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