Non-linear pharmacokinetics of rifampicin in healthy Asian Indian volunteers.

OBJECTIVE: To characterise the pharmacokinetics of rifampicin (RMP) in healthy Asian Indian volunteers after oral administration of commercially marketed reference formulations. DESIGN: Two separate studies were conducted. In Study 1, 12 volunteers were administered a single 450 mg sugar-coated tablet, and in Study 2, 11 volunteers were administered a 30 ml suspension (100 mg/5 ml) equivalent to a 600 mg dose of RMP. Blood samples were collected at 0 hours and then at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 hours post dose, and plasma concentrations were assayed by high performance liquid chromatography. RESULTS: Non-compartmental analysis indicated that the mean (coefficient of variation [%CV]) values for the tablet for Cmax, Tmax and AUC(0-infinity) were 8.59 (53.66) microg/ml, 1.58 h and 49.54 (61.79) microg x h/ml, respectively. The corresponding mean (%CV) values for the suspension were 14.76 (24.14) microg/ml, 1.45 h and 119.12 (28.24) microg x h/ml. Two-compartment analysis indicated that the mean (%CV) values for Cl/F, beta and t(1/2beta) were respectively 197.51 (46.58) (ml/h)/kg, 0.2153 (32.01) h(-1) and 3.57 (34.85) h, at the 450 mg dose (tablet), and were significantly different from the respective 94.76 (33.96) (ml/h)/kg, 0.1210 (33.66) h(-1) and 5.44 (16.69) h at the 600 mg dose (suspension) (P < 0.05). In addition, there was a significant linear correlation (r = 0.60, P < 0.005, n = 21) between Cmax and the elimination half-life, indicating a concentration-dependent increase in half-life. CONCLUSION: Rifampicin obeys two-compartment kinetics with zero order absorption, and exhibits non-linear saturable elimination kinetics as well as large inter-individual variability.

The effect of food on the bioavailability of ibuprofen and flurbiprofen from sustained release formulations.

The effect of food on the plasma concentration-time profile of sustained release dosage forms of ibuprofen and flurbiprofen has been investigated in healthy Asian Indian volunteers, in two separate studies. In study 1, 20 volunteers were administered a single 200 mg multiple-unit sustained release capsule of flurbiprofen (Froben SR), after an overnight fast or a heavy vegetarian breakfast. Food produced a statistically significant increase in the mean (+/-SE) maximal plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-48). Cmax (+/-SE) increased from 9.88 +/- 0.48 mg L-1 (fasting) to 11.36 +/- 0.88 mg L-1 (postprandial) and AUC0-48 (+/-SE) increased from 120.78 +/- 9.64 mg h L-1 (fasting) to 149.73 +/- 12.24 mg h L-1 (postprandial). The mean (+/-SE) time to peak (tmax) was also significantly delayed from 3.85 +/- 0.27 h to 8.70 +/- 0.89 h. In study 2, 18 volunteers were administered a single 800 mg erodible sustained release matrix tablet of ibuprofen (Brufen Retard), after an overnight fast or along with a heavy vegetarian breakfast. The formulation exhibited multiple peaks (n > or = 2) on the plasma concentration-time curve. Although food did not affect the bioavailability of this formulation, there was a statistically significant increase in the mean (+/-SE) concentration of the first peak (Cpeak 1) from 14.21 +/- 1.38 mg L-1 (fasting) to 20.14 +/- 1.38 mg L-1 (with food). The time at which Cpeak 1 was reached was not influenced by the intake of food. Results indicate that while qualitative changes in the plasma concentration versus time curves are primarily influenced by the nature of the formulation and the type of meal, bioavailability is influenced by the absorption characteristics of the drug as well. Thus, despite a significant increase in peak plasma concentrations of both drugs with a meal, the bioavailability of flurbiprofen alone was enhanced.

Comparative pharmacokinetics and amoebicidal activity of metronidazole and satranidazole in the golden hamster, Mesocricetus auratus.

The pharmacokinetic properties of metronidazole and satranidazole were studied in the golden hamster (Mesocricetus auratus), at a dose of 80 mg/kg po. Blood and liver samples were collected at frequent time intervals and assayed for metronidazole and satranidazole by HPLC. Satranidazole exhibited significantly higher plasma concentrations than metronidazole at 1 and 2 h post-dose, but the comparative Cmax values were not significantly different. The satranidazole plasma elimination half-life of 1.01 h was significantly shorter than the corresponding metronidazole half-life of 3.62 h. The comparative liver pharmacokinetic parameters Cmax, Tmax and T1/2 did not differ significantly. Satranidazole however exhibited significantly higher liver concentrations at 1 h post-dose and Cmax and AUC0-infinity values were approximately 35% higher. The in-vivo amoebicidal activity of both compounds was evaluated in the acute hamster hepatic model of amoebiasis. Both metronidazole and satranidazole were administered as single graded doses po, and their dose-response profiles were characterized. Satranidazole demonstrated significantly greater amoebicidal activity than metronidazole with an ED50 value of 19.5 mg/kg, compared to an ED50 value of 45 mg/kg for metronidazole. These data suggest that higher plasma and liver concentrations of satranidazole and greater intrinsic potency probably contribute to superior amoebicidal activity in the hamster model of hepatic infection.

Pharmacokinetics and amoebicidal activity of (+-)-(E)-3-(4- methylsulphinylstyryl)-1,2,4-oxadiazole (BTI 2286E) and its sulphone metabolite (BTI 2571E) in the golden hamster, Mesocricetus auratus.

BTI 2286E is a 1,2,4-oxadiazole with amoebicidal activity. Three groups of golden hamsters received single doses of BTI 2286E or its sulphone metabolite BTI 2571E as either BTI 2286E 60 mg/kg po or BTI 2571E 60 mg/kg po or BTI 2571E 60 mg/kg ip. Blood samples were collected up to 8 h post-dose and plasma concentrations of BTI 2286E and BTI 2571E were assayed by HPLC. BTI 2286E was rapidly absorbed, extensively metabolized during first pass and rapidly eliminated with a plasma elimination half-life of 1.32 h. Conversion to BTI 2571E was the major pathway of elimination. BTI 2571E had approximately 40% bioavailability after oral administration. After intraperitoneal administration its absorption was slow and prolonged, with an apparent elimination half-life of 2.77 h, considerably longer than the elimination half-life of 0.67 h observed when BTI 2571E was formed as a metabolite, in vivo. The amoebicidal activity of both the compounds was evaluated in the acute hamster hepatic model of amoebiasis. Both BTI 2286E and BTI 2571E were administered as single graded po or ip dose, and their dose-response profiles were characterized. BTI 2571E exhibited poor activity after oral administration (ED50 70 mg/kg) probably due to poor bioavailability, but after intraperitoneal administration its activity (ED50 40 mg/kg) was comparable to that of BTI 2286E after po or ip administration.