Comparative pharmacokinetics of four active components on normal and diabetic rats after oral administration of Gandi capsules

The Gandi capsule, a famous traditional Chinese medicine (TCM), is a hospital preparation that has been widely used in China for decades for the treatment of diabetes. The aim of this study is to compare the pharmacokinetics of four of the active components of Gandi capsules, which are the primary antidiabetic ingredients, on normal and diabetic Sprague-Dawley rats following oral administration of the capsules. Baicalin, wogonoside, wogonin, loganin and puerarin (internal standard) were prepared using methanol precipitation, and the separation of the five components was achieved through a ZORBAX Eclipse Plus C₁₈ column by gradient elution using water (containing 0.1% formic acid) and acetonitrile as the mobile phase. After oral administration of Gandi capsules to the normal and diabetic rats, plasma was harvested and analyzed using liquid chromatography coupled with tandem mass spectrometry, and the primary pharmacokinetic parameters were calculated by DAS 2.0. Compared with the normal group, some pharmacokinetic parameters especially the AUC_{0–48 h} of the four compounds significantly increased in the diabetic groups. The results demonstrated that the four constituents in normal and diabetic rats had obvious differences in some pharmacokinetic characteristics, suggesting that the rate and extent of drug metabolism were altered in diabetic animals. The results could be helpful for demonstrating the compatibility mechanism and providing clinical medication guidance for Gandi capsules.

The Gandi capsule, a famous traditional Chinese medicine (TCM), is a hospital preparation that has been widely used in China for decades for the treatment of diabetes.     

Volatile components in Yinchenzhufu decoction and their pharmacokinetics after oral administration in rats

In China, Yinchenzhufu decoction (YCZFD) has been used to treat cholestatic liver disease in clinical practice for hundreds of years. Nonvolatile components in YCZFD, their composition, components absorbed in blood, and pharmacokinetic characteristics have been clarified. However, information about its volatile components is limited. The aim of the present study was to identify the components of the volatile oil (VO) of YCZFD, quantify the major volatile components in YCZFD, and reveal their pharmacokinetic characteristics. In YCZFD, 85 components representing 95.36% of the total oil composition were identified by gas chromatography-mass spectrometry. Next, 11 highly abundant components were quantified in YCZFD and YCZFD VO. Finally, a sensitive headspace solid-phase dynamic extraction-chromatography-quadruple mass spectrometry method for determining 8 volatile components in rat plasma was established and applied to compare the pharmacokinetics of YCZFD and YCZFD VO after oral administration in rats. These volatile components were rapidly absorbed and eliminated, and they presented highly different exposure levels. The area under the concentration–time curves of some volatile components in YCZFD was higher than that in YCZFD VO. The results showed that the water extract of YCZFD increased the exposure of volatile components. Our study provides valuable information for understanding the potential effective components of YCZFD.

In YCZFD, 85 volatile components (VCs) were identified and 11 VCs were quantified by GC-MS/MS. An HS-SPDE-GC-MS/MS method for determining 8 VCs in rat plasma was established and applied to compare the pharmacokinetics of YCZFD and its volatile oil.     

Dose-dependent pharmacokinetics of itraconazole after intravenous or oral administration to rats: intestinal first-pass effect

The dose-dependent pharmacokinetics of itraconazole after intravenous (10, 20, or 30 mg/kg) and oral (10, 30, or 50 mg/kg) administration and the first-pass effects of itraconazole after intravenous, intraportal, intragastric, and intraduodenal administration at a dose of 10 mg/kg were evaluated in rats. After intravenous administration at a dose of 30 mg/kg, the area under the plasma concentration-time curve from time zero to infinity (AUC(0- infinity )) was significantly greater than those at 10 and 20 mg/kg (1,090, 1,270, and 1,760 micro g. min/ml for 10, 20, and 30 mg/kg, dose-normalized at 10 mg/kg). After oral administration, the AUC(0- infinity ) was significantly different for three oral doses (380, 687, and 934 micro g. min/ml for 10, 30, and 50 mg/kg, respectively, dose-normalized at 10 mg/kg). The extent of absolute oral bioavailability (F) was 34.9% after an oral dose at 10 mg/kg. The AUC(0- infinity ) (or AUC(0-8 h)) values were comparable between intravenous and intraportal administration and between intragastric and intraduodenal administration, suggesting that the hepatic and gastric first-pass effects were almost negligible in rats. However, the AUC(0-8 h) values after intraduodenal and intragastric administration were significantly smaller than that after intraportal administration, approximately 30%, suggesting that the intestinal first-pass effect was approximately 70% of that of an oral dose of 10 mg/kg. The low F after oral administration of itraconazole at a dose of 10 mg/kg could be mainly due to the considerable intestinal first-pass effect.     

Plasma and oral fluid pharmacokinetics and pharmacodynamics after oral codeine administration

BACKGROUND: The ease, noninvasiveness, and safety of oral fluid collection have increased the use of this alternative matrix for drugs-of-abuse testing; however, few controlled drug administration data are available to aid in the interpretation of oral fluid results. METHODS: Single oral codeine doses (60 and 120 mg/70 kg) were administered to 19 volunteers. Oral fluid and plasma were analyzed for free codeine, norcodeine, morphine, and normorphine by solid-phase extraction combined with gas chromatography-mass spectrometry (SPE/GC-MS). Physiologic and subjective effects were examined. RESULTS: Mean (SE) peak codeine concentrations were 214.2 +/- 27.6 and 474.3 +/- 77.0 micro g/L in plasma and 638.4 +/- 64.4 and 1599.3 +/- 241.0 micro g/L in oral fluid. The oral fluid-to-plasma ratio for codeine was relatively constant ( approximately 4) from 1 to 12 h. The mean half-life (t(1/2)) of codeine was 2.2 +/- 0.10 h in plasma and 2.2 +/- 0.16 h in oral fluid. Significant dose-related miosis and increases in sedation, psychotomimetic effect, and "high" occurred after the high dose. Mean codeine oral fluid detection time was 21 h with a 2.5 microg/L cutoff, longer than that of plasma (12-16 h). Detection times with the proposed Substance Abuse and Mental Health Services Administration cutoff (40 microg/L) were only 7 h. Norcodeine, but not morphine or normorphine, was quantified in both plasma and oral fluid. CONCLUSIONS: The disposition of codeine over time was similar in plasma and oral fluid, but because of high variability, oral fluid codeine concentrations did not reliably predict concurrent plasma concentrations. Oral fluid testing is a useful alternative matrix for monitoring codeine exposure with a detection window of 7-21 h for single doses, depending on cutoff concentrations. These controlled drug administration data should aid in the interpretation of oral fluid codeine results.     

Comparative pharmacokinetics of ceftriaxone after subcutaneous and intravenous administration

The pharmacokinetics of ceftriaxone (CRO) after subcutaneous and intravenous administration was studied in 10 healthy volunteers (5 males, 5 females, age 22-43 years, body weight 64.3 +/- 9.5 kg). Each of them received 2.0 g CRO i.v., and then 0.5 g i.v. and 0.5 g CRO s.c. in a randomized cross-over design. Subcutaneous administration of ceftriaxone was tolerable in combination with lidocaine. Serum and urine concentrations were determined by high performance liquid chromatography and for comparison with a bioassay. Mean serum concentrations were high after intravenous administration: 258 +/- 40 mg/1 (0 min, 2 g i.v.) resp. 84 +/- 40 mg/1 (0 min, 0.5 g i.v.). They declined to 11.6 +/- 4.2 mg/1 (2 g) resp. 6.5 +/- 2.2 mg/1 (0.5 g i.v.) within 24 h. Following subcutaneous application peak serum concentrations of 37.1 +/- 5.6 mg/1 were found after 138 +/- 49 min and a mean serum concentration of 6.6 +/- 1.6 mg/1 after 24 h. Concentrations of free ceftriaxone, determined by ultrafiltration, were 9.2 +/- 2.7% of total concentrations from 25 to 200 mg/1. Cumulated urine recoveries over a period of 24 h were: 51.2 +/- 8.9% (2 g i.v.), 47.1 +/- 7.9% (0.5 g i.v.) and 39.7 +/- 9.5% (0.5 g s.c.). There was no evidence for the presence of a microbiologically active metabolite in urine. Comparison of pharmacokinetic parameters for the 0.5 g dose did not show relevant differences between intravenous and subcutaneous administration (using an open two-compartment model): t beta 1/2 (min) 514 +/- 104 (s.c.), 592 +/- 133 (i.v.), VD,Area (1) 11.9 +/- 3.8 (s.c.), 13.3 +/- 3.8 (i.v.) and AUCtot (mg X h/1) 515 +/- 106 (s.c.) and 549 +/- 125 (i.v.). Bioavailability of the subcutaneous application was 0.96 +/- 0.26. For the 2 g i.v. dose the known nondosis-dependent kinetics was observed. Subcutaneous administration of ceftriaxone appears to be a possible alternative to the intravenous route in selected clinical situations or cases.     

Vanadium pharmacokinetics and oral bioavailability upon single-dose administration of vanadyl sulfate to rats

Vanadium pharmacokinetic parameters and oral bioavailability were determined after administration of vanadyl sulfate, an antidiabetic agent, to male Wistar rats. An optimal sampling design was used over a 21-day period; vanadium was measured in blood by atomic absorption spectrophotometry (AAS). After i.v. bolus injection (3.025 mg V/kg body weight), a three-compartment model was fitted to the data. Mean (+/- SD) half-lives were 0.90 +/- 0.56 hours, 24.8 +/- 14.5 h and 201 +/- 74 h, respectively, for the three phases observed. Vanadium clearance averaged 37.6 +/- 15.8 mL/h. Initial volume of distribution was 2.43 +/- 1.22 L/kg whereas total volume of distribution was 25.4 +/- 3.9 L/kg; these values largely exceeded body weight (i.e. 300 g), in agreement with a great uptake and retention of vanadium in tissues. After oral gavage administration (15.12 and 7.56 mg V/kg body weight), vanadium disposition was best described by a three-compartment model, with absorption appearing to occur by a zero-order rate. This process lasted 10.3 +/- 1.3 h and 10.9 +/- 1.1 h for the two dosage levels, respectively. Half-lives corresponding to the terminal log-linear part of the curve were 173.5 +/- 1.6 h and 172 +/- 6 h (Bayesian estimates). No dose-dependency was observed for any of the parameters determined. Absolute bioavailabilities, with reference to the i.v. administration, were 12.5% and 16.8% when determined from AUCmod. Bioavailability appeared to be higher than generally stated in the literature.     

Pharmacokinetic and excretion study of three alkaloids in rats using UPLC-MS/MS after oral administration of menispermi rhizoma capsules

A sensitive, specific and rapid ultra-performance liquid chromatography tandem mass spectrometry method (UPLC-MS/MS) was developed for simultaneous determination of three main alkaloids (daucicoline, daurisoline, dauricine) in rat plasma, urine and feces after oral administration of menispermi rhizoma capsules. The chromatographic separation was performed on a Waters ACQUITY UPLC® BEH C₁₈ column (50 mm × 2.1 mm, id, 1.7 μm) with a column temperature of 30 °C and a linear gradient elution using a mobile phase consisting of 0.1% formic acid and acetonitrile. The flow rate was set at 0.3 mL min⁻¹, and the total run time was 10 min. The detection was performed, without interference, using positive electrospray ionization with a multiple reaction monitoring mode. A comprehensive validation of the method was performed. The linearity of the analytical response was good over a wide concentration range with correlation coefficients greater than 0.9903 and the lower limits of quantification were 1.5–5.0 ng mL⁻¹ for all matrices. Both accuracy and precision of the assay were satisfactory. The mean extraction recoveries of analytes and internal standard from rat plasma, urine and feces were all more than 78.3%. The validated methods of the three types of substrates were successfully applied to a pharmacokinetic and excretion study of the three alkaloids in rats after oral administration of menispermi rhizoma capsule. The pharmacokinetics and excretion study of these active components in menispermi rhizoma capsule have not been reported. The results provided a meaningful basis for the clinical application of menispermi rhizoma capsule.

A sensitive, specific and rapid UPLC-MS/MS was developed for simultaneous determination of three main alkaloids (daucicoline, daurisoline, dauricine) in rat plasma, urine and feces after oral administration of menispermi rhizoma capsules.     

Comparative pharmacokinetics and tissue penetration of sulbactam and ampicillin after concurrent intravenous administration

A combination of 500 mg each of sulbactam and ampicillin was administered intravenously into six healthy male volunteers, and subsequent serum and blister fluid levels were measured. Both dogs had similar serum half-lives of about 1 h. The concentrations of sulbactam in serum and blister fluid were about 1.5 times those of ampicillin, and appeared to be pharmacokinetically well matched when administered in equal doses.     

Comparative oral pharmacokinetics of fleroxacin and pefloxacin

The pharmacokinetics of a single 400 mg oral dose of fleroxacin and pefloxacin were evaluated in ten healthy male volunteers in a randomized cross-over study. There were no significant differences in Tmax (0.9 vs. 1.3 h) and in plasma elimination half-life (11.9 vs. 10.8 h) between fleroxacin and pefloxacin. Cmax and AUC of fleroxacin were statistically significantly greater (P less than 0.05) compared to pefloxacin (Cmax: 5.62 vs. 4.09 mg/l, AUC0-48: 65.9 vs. 48.7 mg/l.h, AUC0-infinity: 70.7 vs. 51.5 mg/l.h). Renal clearances of fleroxacin and pefloxacin were 51.8 and 11.7 ml/min respectively. The 48-h urine recovery was 48.6% for fleroxacin, 8.6% for pefloxacin, 7.1% and 17.4% for the N-demethyl metabolites, and 3.8% and 16.6% for the N-oxide metabolites of fleroxacin and pefloxacin respectively. Urinary concentrations of both the microbiologically active parent drug and the N-demethyl metabolite of fleroxacin were, at all intervals up to 48 h post dose, two to three times higher than those of pefloxacin.     

Methamphetamine and amphetamine pharmacokinetics in oral fluid and plasma after controlled oral methamphetamine administration to human volunteers

BACKGROUND: Methamphetamine (METH) and amphetamine (AMP) concentrations in 200 plasma and 590 oral fluid specimens were used to evaluate METH pharmacokinetics and pharmacodynamics after oral administration of sustained-release METH. METHODS: Eight participants received four oral 10-mg S-(+)-METH hydrochloride sustained-release tablets within 7 days. Three weeks later, five participants received four oral 20-mg doses. Blood samples were collected for up to 24 h and oral fluid for up to 72 h after drug administration. RESULTS: After the first oral dose, initial plasma METH detection was within 0.25-2 h; c(max) was 14.5-33.8 micro g/L (10 mg) and 26.2-44.3 micro g/L (20 mg) within 2-12 h. In oral fluid, METH was detected as early as 0.08-2 h; c(max) was 24.7-312.2 micro g/L (10 mg) and 75.3-321.7 micro g/L (20 mg) and occurred at 2-12 h. The median oral fluid-plasma METH concentration ratio was 2.0 across 24 h and was highly variable. Neutral cotton swab collection yielded significantly higher METH and AMP concentrations than citric acid candy-stimulated expectoration. Mean (SD) areas under the curve for AMP were 21% +/- 25% and 24% +/- 11% of those observed for METH in plasma and oral fluid, respectively. After a single low or high dose, plasma METH was >2.5 micro g/L for up to 24 h in 9 of 12 individuals (mean, 7.3 +/- 5.5 micro g/L at 24 h); in oral fluid the detection window was at least 24 h (mean, 18.8 +/- 18.0 micro g/L at 24 h). The plasma and oral fluid 24-h METH detection rates were 54% and 60%, respectively. After four administrations, METH was measurable for 36-72 h (mean, 58.3 +/- 14.5 h). CONCLUSIONS: Perceived advantages of oral fluid for verifying METH exposure compared with urine include simpler specimen collection and reduced potential for adulteration, but urine offers higher analyte concentrations and a greater window of detection.     

Effect of famotidine on ciprofloxacin pharmacokinetics after single intravenous and oral doses in rats

The effect of intravenous (3.5 mg/kg) and oral (5 mg/kg) famotidine on ciprofloxacin pharmacokinetics after single (i.v.) intravenous (5 mg/kg) and oral (20 mg/kg) doses were examined in the rat. Famotidine co-administration significantly increased the terminal elimination half-life of ciprofloxacin (54% and 29% following i.v. and oral administration, respectively) and tended to reduce the total body clearance by 27% and 34% following i.v. and oral routes, respectively. The area under the plasma concentration-time curve and the mean residence time in the body after i.v. and oral doses were significantly increased following famotidine co-administration. No changes in the steady-state apparent volume of distribution was observed after i.v. administration. The maximum plasma concentration and the time to peak concentration after oral dosing were also unaffected. These results suggest a possible reduction in the total clearance of ciprofloxacin, owing to inhibition of its renal tubular excretion by famotidin. Further studies are warranted to determine whether this interaction occurs in humans.     

Pharmacokinetics of fluconazole in saliva and plasma after administration of an oral suspension and capsules.

The concentrations of fluconazole were determined at steady state in the saliva and plasma of 10 healthy volunteers after ingestion of fluconazole as capsules and after flushing the mouth for 2 min with the same dose formulated as an oral suspension and swallowing of the drug. Saliva and plasma samples were analyzed by a validated high-performance liquid chromatographic assay. Flushing and swallowing of the oral suspension resulted in a significantly (P = 0.005) higher mean area under the concentration-versus-time curve (AUC) from 0 to 24 h in saliva (89.13 +/- 23.42 mg.h/liter) than that obtained after ingestion of the same dose as capsules (69.27 +/- 12.89 mg . h/liter). The calculated mean maximum concentration in saliva just after swallowing of the suspension was 97.99 +/- 6.12 mg/liter. The peak fluconazole concentration in saliva after the ingestion of the capsules was 3.55 +/- 0.40 mg/liter. The fluconazole oral suspension and capsules resulted in comparable concentrations and AUCs in plasma. Thus, because of a higher local level of drug exposure in terms of both higher peak concentrations in saliva and a higher salivary AUC, the fluconazole oral suspension has theoretical advantages over the capsule formulation in the treatment of oropharyngeal candidiases.     

Comparative pharmacokinetics of ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, trovafloxacin, and moxifloxacin after single oral administration in healthy volunteers

In an open, randomized, six-period crossover study, the pharmacokinetics of ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin were compared after a single oral dose in 12 healthy volunteers (6 men and 6 women). The volunteers received 250 mg of ciprofloxacin, 400 mg of gatifloxacin, 600 mg of grepafloxacin, 500 mg of levofloxacin, 400 mg of moxifloxacin, and 200 mg of trovafloxacin. The concentrations of the six fluoroquinolones in serum and urine were measured by a validated high-performance liquid chromatography method. Blood and urine samples were collected before and at different time points up to 48 h after medication. Levofloxacin had the highest peak concentration (C(max), in micrograms per milliliter) (6.21+/-1.34), followed by moxifloxacin (4.34+/-1.61) and gatifloxacin (3.42+/-0.74). Elimination half-lives ranged from 12.12+/-3.93 h (grepafloxacin) to 5.37+/-0.82 h (ciprofloxacin). The total areas under the curve (AUC(tot), in microgram-hours per milliliter) for levofloxacin (44.8+/-4.4), moxifloxacin (39.3+/-5.35), and gatifloxacin (30+/-3.8) were significantly higher than that for ciprofloxacin (5.75+/-1.25). Calculated from a normalized dose of 200 mg, the highest C(max)s (in micrograms per milliliter) were observed for levofloxacin (2.48 +/-0.53), followed by moxifloxacin (2.17+/-0.81) and trovafloxacin (2.09+/-0.58). The highest AUC(tot) (in microgram-hours per milliliter) for a 200-mg dose were observed for moxifloxacin (19.7+/-2.67) and trovafloxacin (19.5+/-3.1); the lowest was observed for ciprofloxacin (4.6+/-1.0). No serious adverse event was observed during the study period. The five recently developed fluoroquinolones (gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin) showed greater bioavailability, longer half-lives, and higher C(max)s than ciprofloxacin.     

Enantioselective pharmacokinetics of 10-hydroxycarbazepine after oral administration of oxcarbazepine to healthy Chinese subjects

BACKGROUND AND OBJECTIVES: Oxcarbazepine is a new antiepileptic drug which in humans acts as a prodrug to its central nervous system-active metabolite 10-hydroxycarbazepine. Because 10-hydroxycarbazepine is a chiral molecule, the objective of the study was to perform a stereoselective pharmacokinetic analysis of 10-hydroxycarbazepine in humans. METHODS: The pharmacokinetics and disposition of the enantiomers of 10-hydroxycarbazepine were investigated in 12 healthy Chinese subjects. Each subject received a single oral dose of 600 mg oxcarbazepine and the concentrations of R- and S-10-hydroxycarbazepine in serum were determined by a stereoselective HPLC assay. The enantiomers of free and conjugated 10-hydroxycarbazepine and of the oxidized diol metabolite were also quantified in urine. (con 't on page 548) RESULTS: At all sampling times, the serum concentrations of S-10-hydroxycarbazepine were much higher than those of R-10-hydroxycarbazepine, and their ratio also tended to increase with time. The area under the serum concentration versus time curve of S-10-hydroxycarbazepine was about fivefold greater than that of R-10-hydroxycarbazepine (129.8 +/- 33.1 versus 26.3 +/- 8.5 mg/L x h; P < .001). Half-lives did not differ significantly between the enantiomers (11.9 +/- 3.3 hours for R-10-hydroxycarbazepine versus 13.0 +/- 4.1 hours for S-10-hydroxycarbazepine). About 27% of the molar dose of oxcarbazepine was recovered in urine, mostly as the S-enantiomer of 10-hydroxycarbazepine and its conjugates. Carbamazepine-10,11-trans-dihydrodiol accounted for less than 3% of urinary metabolites. CONCLUSIONS: The marked differences in serum levels and urinary excretion between the two enantiomers of 10-hydroxycarbazepine are likely to be related primarily to stereoselective presystemic metabolic keto-reduction of the prochiral carbonyl group of the oxcarbazepine molecule.     

Faecal elimination of steroids in rats after oral administration of mepartricin

Treatment of both male and female rats with 5 IU/day mepartricin for 7-10 days administered by gastric tubing resulted in an increased faecal excretion of some steroids. Mean rate of elimination of total oestrogens was enhanced by 45% in male rats and by 14% in female rats, and the average excretion of conjugated oestrogen was also increased in the female animals. Faecal elimination of cholesterol was 37% and 42% higher in male and female rats, respectively, after mepartricin treatment, and in male rats plasma concentrations of cholesterol were reduced following treatment. It is suggested mepartricin acts either by changing the intestinal flora or by acting directly on the steroid moieties, and it is speculated that a similar mechanism may occur in man.     

Comparative pharmacokinetics of azlocillin and piperacillin in normal adults

The single-dose pharmacokinetics of azlocillin and piperacillin were compared by using a randomized, crossover design. The concentrations of azlocillin in serum were consistently higher than those of piperacillin throughout an 8-h study. The area under the time-concentration curve of azlocillin was significantly greater than that of piperacillin, and the total body clearance of azlocillin was significantly lower than that of piperacillin.     

Comparative pharmacokinetics of amphotericin B after administration of a novel colloidal delivery system, ABCD, and a conventional formulation to rats.

The pharmacokinetics and tissue distribution of two amphotericin B dosage forms were compared in rats. A novel lipid-based colloidal delivery system for amphotericin B (Amphotericin B Colloidal Dispersion [ABCD]) which reduces the toxicity of amphotericin B in animals was compared with a conventional micellar formulation. Male Sprague-Dawley rats received a single intravenous injection of 1.0 mg of ABCD, 5.0 mg of ABCD, or 1.0 mg of micellar amphotericin B per kg. Plasma and tissue samples were obtained at 0.5 to 96 h after dosing and analyzed for amphotericin B by high-pressure liquid chromatography. Animals receiving ABCD demonstrated reduced peak levels in plasma, a three- to sevenfold reduction in amphotericin B delivery to the kidneys (the major target organ for toxicity), and prolonged residence time compared with those receiving the micellar formulation. In contrast, amphotericin B concentrations in the liver were two- to threefold higher with ABCD than with the micellar formulation: nearly 100% of the amphotericin B administered as ABCD was recovered from the liver 30 min after dosing. These results suggest that the colloidal particles of ABCD are taken up by the liver, which then acts as a reservoir of amphotericin B.     

Effect of oral antacid administration on the pharmacokinetics of intravenous doxycycline.

The effect of oral antacid administration on the pharmacokinetics of intravenous doxycycline was studied. In a randomized crossover design, six healthy male volunteers received an infusion of 200 mg of doxycycline hyclate on two occasions separated by 7 days. On one occasion, subjects were given 30 ml of aluminum hydroxide orally four times a day for 4 days, beginning 2 days prior to doxycycline dosing. Blood and urine samples were collected up to 48 and 96 h after the infusion, respectively, and were analyzed by a microbial assay. Values for volume of distribution at steady state, nonrenal clearance, urine recovery, and urine pH were not statistically different among treatment groups. With concomitant antacid therapy, the half-life of intravenous doxycycline was shortened from 16.2 +/- 2.6 to 11.2 +/- 1.2 h (P = 0.003), and total body clearance increased from 37.4 +/- 6.5 to 54.1 +/- 12.3 ml/min (P = 0.008). Area under the concentration-time curve for serum was decreased by 18 to 44%, with a 22 to 41% increase in renal clearance. Although the increase in nonrenal clearance ranged from 11 to 128%, the high variability led to a nonsignificant difference (P = 0.07). Concomitant oral antacid therapy may significantly enhance the clearance of intravenous doxycycline.