• Archives of Pharmacal Research
• /
• v.23 no.4
• /
• pp.374-380
• /
• 2000

Propentofylline (PPF, 3-methyl-1-(5-oxohexyl)-7-propylxanthine) has been reported to be a compound for treatment of both vascular dementia and dementia of the Alzheimer type. The short half-life (about 15 min) of PPF at the terminal elimination phase and poor bioavailability after oral administration of PPF to rabbits (Kim et al., 1992) suggest in part that this drug takes the extensive first-pass metabolism in the liver. In addition, the metabolic pathway for PPF remains unclear. The objective of this experiment is to identify urinary metabolites of PPF in rats. For the identification of the metabolites, rat urine was collected after oral administration of 100${m}g/kg$ PPF. PPF metabolite, 3-methyl-1-(5-hydroxyhexyl)-7-propylxanthine, was synthesized and confirmed by gas chromatography/mass spectroscopy (GC/MS) and $^1H$ nuclear magnetic resonance spectroscopy. The urinary metabolites of PPF were extracted with diethyl ether and identified by electron impact and chemical ionization GC/MS. One urinary metabolite was confirmed to be 3-methyl-1-(5-hydroxyhexyl)-7-propylxanthine by synthesized authentic compound. Several metabolites of monohydroxy- and dihydroxy-PPF were identified based on mass fragmentation of both intact and trimethylsilylated derivatives of PPF metabolites and the novel structure of these metabolites is suggested based on mass spectra.

• Archives of Pharmacal Research
• /
• v.21 no.6
• /
• pp.698-702
• /
• 1998

Propentofylline (PPF, 3-methyl-1-(5-oxohexyl)-7-propylxanthine) has been reported to be effective for the treatment of both vascular dementia and dementia of the Alzheimer type. The pharmacological effects of PPF may be exerted via the stimulation of nerve growth factor, increased cerebral blood flow, and inhibition of adenosine uptake. The objectives of this experiment are to determine the kinetic behavior of PPF, to identify, and to quantify its metabolite in human. Blood samples were obtained from human volunteers following oral administration of 200mg of PPF tablets. For the identification and quantification of the metabolite, 3-methyl-1-(5-hydroxyhexyl)-7-propylxanthine (PPFOH), PPFOH was synthesized and identified by gas chromatography/mass spectroscopy (GC/MS) and $^1H$-nuclear magnetic resonance spectroscopy. The molecular weight of synthesized metabolite is 308 dalton. The PPF and PPFOH in plasma were extracted with diethyl ether and identified by electron impact GC/MS. The plasma concentrations of PPF and PPFOH were determined by gas chromatography/nitrogen phosphorus detector in plasma and their pharmacokinetic parameters were determined. The mean half-life of PPF was 0.74 hr. The areas under the curve (AUCs) of PPF and PPFOH were 508 and 460ng.hr/ml, respectively. $C_{max}$ of PPF was about 828.4ng/ml and the peak concentration was achieved at about 2.2 hr ($T_{max}$). These results indicate that PPF is rapidly disappeared from blood due to extensive metabolism into PPFOH.

• The Korean Journal of Pain
• /
• v.33 no.4
• /
• pp.326-334
• /
• 2020

Background: In this study, we sought to evaluate whether systemic propentofylline (PPF) has antiallodynic effects in a rat model of postoperative pain, and to assess the mechanism involved. Methods: After plantar incision, rats were intraperitoneally injected with various doses of PPF to evaluate its antiallodynic effect. To investigate the involved mechanism, rats were intraperitoneally injected with yohimbine, dexmedetomidine, prazosin, naloxone, atropine or mecamylamine, following the incision of the rat hind paws, and then PPF was administered intraperitoneally. The mechanical withdrawal threshold (MWT) was evaluated using von Frey filaments at various time points and serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were measured to determine the inflammatory response level. Results: MWT was significantly increased after intraperitoneal injection of 30 mg/kg of PPF when compared with the control group. Injection of PPF and yohimbine, atropine or mecamylamine showed significant decreases in the MWT, while injection of PPF and dexmedetomidine showed a significant increase. Systemic administration of PPF inhibited the post-incisional increase in serum level of TNF-α and IL-1β. Conclusions: Systemic administration of PPF following surgery presented antiallodynic effects in a rat model of postoperative pain. The antiallodynic effects against mechanical allodynia could be mediated by α-adrenergic and cholinergic receptors.

• Proceedings of the Korean Society of Applied Pharmacology
• /
• 1998.11a
• /
• pp.122-122
• /
• 1998

Propentofylline (PPF), a xanthine derivative, has been reported to be effective for the treatment of both vascular dementia and Alzheimer's disease. The elimination half-life of PPF was ranged from 15 to 45 min in rabbit and human, and PPF was rapidly disappeared from the blood. The objective of this experiment is to investigate whether xanthine analogues have effects on the profile of plasma concentration and metabolism of PPF. Caffeine (50 mg/kg, ip) was treated to Sprague-Dawley rats for consecutive 7 days and PPF was intravenously administered to rats 2 hr after the last dose of caffeine. In the other group, PPF was intravenously administered to rats 1 hr after a single dose of pentoxifylline (50 mg/kg, iv). Control group was treated with saline vehicle for the same period as in treatment groups. Blood was withdrawn at specific time intervals. PPF and one of its metabolite (POH) in plasma were determined by gas chromatography/nitrogen phosphorus detector. Plasma concentrations and pharmacokinetic parameters were compared between groups. The area under the curve (AUC) of PPF in rats treated sub chronically with caffeine was significantly decreased compared to control rats. Caffeine treatment results in a significant increase of total body clearance. The AUC of POH was significantly decreased in the caffeine-treated group. A single dose of pentoxifylline has no effect on the phramacokinetics of PPF. Reduction of the AUCs of PPF and POH both suggests that caffeine may increase the excretion of PPF with no affecting the metabolism of PPF to POH.