Circadian Variations in the Pharmacokinetics of Pentoxifylline in Man

Abstract

Optimization of therapy by chronopharmacology requires knowledge of rhythmic manifestations of disease activity and chronopharmacokinetic data of the drugs prescribed. Rhythmic functioning of the cardiovascular system in healthy and diseased subjects is manifested as circadian rhythms in blood pressure, cardiac output, heart rate, etc. The disposition of several cardiovascular drugs in man has been reported to be time-dependent. This study reports the effect of time of administration on the disposition of pentoxifylline. Twelve healthy volunteers were treated with 400 mg pentoxifylline orally at 0100, 0700, 1300 and 1900 h in a randomized crossover Latin-square design with a wash-out period of one week. Serum samples were analysed for unchanged pentoxifylline by HPLC. Pharmacokinetic parameters were calculated using a model-independent method. The mean values of various pharmacokinetic parameters after drug treatment at these times were, respectively: maximum plasma concentration (Cmax) 485+/-174, 646+/-175, 735+/-271 and 781+/-217 ng mL(-1); time to reach the maximum plasma concentration (Tmax) 1.90+/-0.39, 1.66+/-0.4, 1.31+/-0.41 and 1.32+/-0.44 h, mean residence time (MRT) 3.8+/-0.8, 2.9+/-0.5, 2.9+/-0.4 and 2.7+/-0.3 h, elimination half-life (t1/2) 1.93+/-0.86, 1.23+/-0.3, 1.39+/-0.3 and 1.23+/-0.18 h and volume of distribution at steady state (VdSS/f) 11991+/-4862, 8823+/-3484, 8275+/-2357 and 7063+/-1950 mL kg(-1). The mean Cmax value was significantly (P < 0.05) lower after drug administration at 0100 h than after other time-points whereas mean Tmax, MRT, VdSS/f and t1/2 values were significantly (P < 0.05) higher. These variations might be because of time-dependent changes in absorption and biliary excretion of pentoxifylline and should be borne in mind when designing sustained action dosage forms for the drug.

Suramin augments the antitumor and antimetastatic activity of pentoxifylline in B16F10 melanoma

“…31 In contrast, PTX is cleared off very fast. 32 Therefore, suramin administration followed by PTX is more appropriate as it gives a window where both the drugs are present and can interact. Suramin and PTX treatment for 24 hr showed concentration-dependent inhibition in F10 cell viability.…”

Pharmacokinetics of Pentoxifylline after Oral Administration of a Sustained Release Tablet at Two Different Times of the Day

“…From the above paragraphs it is evident that the time dependent pharmacokinetics of some drugs (nifedipine and isosorbide-5-mononitrate) are masked upon administering them as sustained release dosage froms, whereas in other cases (indometacin, verapamil) even sustained release dosage forms also exhibited chronokinetics. Earlier we have reported (Srinivasu et al 1998) that pentoxifylline given as immediate release capsule exhibited dosing time related changes in its pharmacokinetics resulting in significantly lowered C max and increased T max , Vss/f, T 1/2 and MRT following 01:00 h administration when compared with 07:00, 13:00 and 19:00 h dosing. In the present study similar changes in C max and Vss/f are observed.…”

“…Pentoxifylline (CAS-6493-05-6) owing to its short half-life is generally administered in the form of sustained release tablets for prophylactic as well as therapeutic uses. The chronopharmacokinetics of pentoxifylline following its administration as immediate release capsules was reported earlier (Srinivasu et al 1998). In this study we have investigated the influence of circadian rhythms on the pharmacokinetics of sustained release tablets of pentoxifylline in healthy subjects.…”

Timing in drug absorption and disposition: The past, present, and future of chronopharmacokinetics

“…As urinary elimination was unaffected by dosing time, these variations were attributed to oscillations of hepatic clearance, which encompasses metabolic and biliary clearance (Canal et al, 1991). Identically, Srinivasu, Rao, Rao, and Rambhau (1998) partly attributed the lower C max of pentoxifylline at 01.00 hr to its biliary excretion and extensive enterohepatic circulation (Table 3).…”