Mechanism of drug interaction between a Kampo medicine, byakkokaninjinto, and tetracycline in rats.

We have previously reported that concomitant oral administration of the Kampo medicine, byakkokaninjinto (TJ-34), in extract granules, reduced the plasma concentrations of tetracycline (TC) and ciprofloxacin in humans, which might be the result of forming a chelate with Ca(2+). In the present study, we investigated the effect of a chelating agent, ethylenediaminetetraacetic acid (EDTA), on the plasma concentration-time profiles of TC after coadministration of TJ-34 dried extract and TC in rats to clarify whether metal ions contained in the TJ-34 dried extract contribute to this interaction. TJ-34 dried extract significantly reduced the plasma concentration of TC. The values of maximum concentration (C (max)), area under the plasma concentration-time curve and percentage of urinary recovery (f (e)) of TC were reduced to 42%, 40%, and 45%, respectively. On the other hand, treatment with EDTA significantly counteracted the effect of TJ-34 dried extract to reduce absorption of TC, indicating that metal ions mainly account for the interaction. Next, we investigated the effect of staggered administration of TJ-34 dried extract and TC to avoid the drug interaction between them. Administration of TJ-34 dried extract 2 h before TC had no effect on plasma concentrations and pharmacokinetic parameters of TC. These results provide a precise mechanism of the interaction TJ-34 and TC, suggesting a safe and effective dosage regimen to coadminister TJ-34 and TC in clinical use.

Effect of a Kampo preparation, byakkokaninjinto, on pharmacokinetics of ciprofloxacin and tetracycline.

The effect on the bioavailability of the antimicrobial agents (ciprofloxacin and tetracycline), which are well known to form chelates with cationic metals such as calcium, was evaluated in 20 healthy male volunteers according to an open, random crossover fashion using a Kampo preparation, byakkokaninjinto (TJ-34) which contains various cationic metals including calcium. Each subject received a single oral dose of tetracycline (250 mg) alone or ciprofloxacin (200 mg) alone along with a single coadministration of one pack (3 g) of the Kampo preparation, at one-week intervals. Concentrations of the drugs in plasma and urine were analyzed by HPLC. Concomitant administration of the Kampo preparation significantly decreased the peak plasma concentration (C(max)) and area under the plasma concentration-time curves (AUC), but not time to reach C(max) (T(max)), of ciprofloxacin and tetracycline. However, the decrease in bioavailability of ciprofloxacin was slight (15%) compared with that of tetracycline (30%). The Kampo preparation significantly decreased the urinary recovery of tetracycline, but not ciprofloxacin, and it had no effect on the renal clearance of either ciprofloxacin or tetracycline. These results indicate that the Kampo preparation tested in this study reduces the extent of bioavailability of ciprofloxacin and tetracycline, but not renal excretion, by decreasing the gastrointestinal absorption due to the formation of insoluble chelates with calcium. We recommend that the dose timing of the Kampo preparation should be carefully controlled to avoid therapeutic failure especially for patients receiving the treatment with tetracycline.

Possible involvement of organic anion and cation transporters in renal excretion of xanthine derivatives, 3-methylxanthine and enprofylline.

Whether organic anion and cation transporters are involved in the renal excretion of xanthine derivatives, 3-methylxanthie and enprofylline, remains unclear. In this study, we have investigated the effects of typically predominant substrates for organic anion and cation transporters on the tubular secretion of 3-methylxanthine and enprofylline in rats. In the renal clearance experiments using typical substrates for organic anion transporters, probenecid and p-aminohippurate, probenecid (20 mg/kg), but not p-aminohippurate (100 mg/kg), significantly decreased the renal clearance and clearance ratio of 3-methylxanthine and enprofylline. The typical substrates for organic cation transport systems, tetraethylammonium (30.6 mg/kg) and cimetidine (50 or 100 mg/kg), significantly decreased the renal clearance and clearance ratio of 3-methylxanthine and enprofylline. These results suggest that the renal secretory transport of 3-methylxanthine and enprofylline are mediated by probenecid-, cimetidine- and tetraethylammonium-sensitive transport systems. Uric acid, an organic anion, significantly inhibited the renal secretion of 3-methylxanthine, but not enprofylline, suggesting that the renal tubular transport of 3-methylxanthine is also mediated via uric acid-sensitive transport system. These findings suggest the possibility that both organic anion and cation transporters are, at least, involved in the renal tubular transport of 3-methylxanthine and enprofylline in rats.