Bacterial pyrogens of different origin and pharmacokinetics of rifampicin

Changes of pharmacokinetics of rifampicin (RFP, Rifadin were investigated on endotoxin pretreated still not ruminant calves. The animals served as their own controls and drug administration twice in a 1-week interval gave the same results. Endotoxin 0.02 micrograms kg-1 given intravenously 1 h prior to the oral administration of RFP (20 mg kg-1) induced considerable pharmacokinetic changes. The serum levels of the total drug were significantly lower after the endotoxin administration. The pharmacokinetic analysis revealed significant changes mainly in the distribution phase. When both toxin and drug were administered intravenously, the drug levels were higher. The results are discussed with reference to the pathophysiological endotoxin changes. After the toxin administration the bioavailability of oral RFP was 4-fold lower.     

Serum and urine concentrations of rifampicin administered by intravenous infusion in man

Two studies were carried out in man with the aim of assessing the serum and urine concentrations of rifampicin administered by i.v. infusion. In patients suffering from various diseases, a dose of 600 mg i.v. proved to be equieffective with a 600 mg oral dose. Repeated administration of a 600 mg dose by i.v. infusion for a week produced serum levels corresponding to those achieved by oral administration. With the i.v. preparation the drop in serum rifampicin levels during continuous administration was less marked than with the oral administration. The recovery of antibiotic in the urine seems to be lower with i.v. than with the oral preparation. The i.v. preparation was very well tolerated by all the patients.     

Changes of pharmacokinetics of trimethoprim after pretreatment with streptococcal peptidoglycan

Trimethoprim (TMP) 10 mg.kg-1 was given orally to calves and rabbits. Two to three weeks later the animals were pretreated by i.v. Peptidoglycan (Pt) 20 micrograms.kg-1. One hour later TMP was administered as above. To other animals under otherwise identical conditions TMP was injected intravenously. The pretreatment with Peptidoglycan induced in both species a significant increase of TMP serum levels positively correlated with temperature elevation. Peptidoglycan pretreatment increased the bioavailability of TMP.     

Pharmacokinetic models for the saturable absorption of cefuroxime axetil and saturable elimination of cefuroxime.

Since oligopeptidic drugs such as beta-lactam antibiotics share the same carriers in humans and animals, the absorption and elimination kinetics of cefuroxime (C) were investigated in rats. Plasma C concentrations were measured by liquid chromatography. Pharmacokinetics and bioavailability of C in the rat were examined after intravenous (i.v.) administration at three doses (1.78, 8.9 and 17.8mg) of cefuroxime sodium and oral administration at two doses (2.02 and 8.9mg) of cefuroxime axetil (CA). Preliminary fits using data from intravenous administration of C showed that the drug disposition kinetics were clearly nonlinear, with an increase in plasma clearance as the intravenous dose increased. After oral administration of CA, normalized C(max) was higher for smaller dose than for the largest dose. The population pharmacokinetic parameters were obtained by means of nonlinear mixed effect modelling approach according to a nonlinear elimination and nonlinear absorption two-compartment model. The nonlinear elimination could be attributed to a saturable renal tubular reabsorption of the antibiotic and nonlinear intestinal absorption of CA mediated by carrier system. The oral bioavailability of C, calculated by numeric integration of an amount of CA drug absorbed was 22 and 17% for 2.02 and 8.9mg of prodrug administered orally.     

Pharmacokinetics and tissue distribution of rifametane, a new 3-azinomethyl-rifamycin derivative, in several animal species

Single and repeated dose experiments in mice, rats, dogs and monkeys are reported in this study to assess the pharmacokinetics and tissue distribution of rifametane, a new semi-synthetic rifamycin with the chemical formula 3-[(1-diethylaminoethylidene)azinomethyl]rifamycin SV (CAS 94168-98-6, SPA-S-565). All the kinetic tests were carried out in comparison with known rifamycin derivatives, as rifampicin (CAS 13292-46-1) or rifamycin SV (CAS 6998-60-3). Mice received single i.v. and oral administration of 10 mg/kg of rifametane or of rifampicin and serum samples were obtained up to 96 h after dosing. The two antibiotics showed similar peak of serum concentrations, but rifametane showed a longer half-life and higher AUC values. In an additional experiment, the tissue/serum ratio after the 10 mg/kg oral dose was lower than unity for lungs and kidneys, while the liver/serum ratio exceeded the unity at all sampling times. After 4 weeks of once weekly administration measurable serum and tissue concentrations were observed, and after twice weekly administration for the same time period some blood and tissue accumulation was seen. Rats were treated with a single intravenous injection of 20 mg/kg of rifametane or rifampicin and with single oral or i.m. administration of 60 mg/kg of rifametane or reference standards (rifampicin and rifamycin SV resp.), in two separate trials. The serum half-life of the test antibiotic after i.v. dose was 6 times longer than that of rifampicin and the serum concentrations of rifametane after oral and i.m. doses were higher and longer-lasting than those of the reference compounds. Repeated daily administrations of rifametane at three dose levels (3, 10, 30 mg/kg p.o.) for 4 weeks induced very high serum and liver concentrations. Dogs received a single oral dose of 1.25 mg/kg of rifametane or 2.5 mg/kg of rifampicin. The serum half-life of rifametane resulted 3 times longer than that of rifampicin. Remarkable serum and tissue concentrations were observed after 3-4 weeks of daily oral administration of rifametane at 3, 10, 30 mg/kg dose. Monkeys were given single oral or i.m. administration of 30 mg/kg of rifametane or reference standards (oral rifampicin and i.m. rifamycin SV). The serum concentrations after rifametane were higher and more sustained than those of reference compounds and the half-lives of the test antibiotic were about 2.5 (p.o.) to 6 times (i.m.) longer. The urine excretion of rifametane after a single intravenous dose in rats and a single oral dose in dogs was very low, while rifampicin had a little higher urine concentrations.     

Vibration stress and pharmacokinetics of rifampicin

The influence of horizontal vibration stress on pharmacokinetics of rifampicin (RFP) 20 mg.kg-1 on rabbits was investigated. RFP was given orally or intravenously. The experiments were repeated one week later. The drug was administered immediately after 60 min of vibration like in control experiments on the same animals. Another group of animals was exposed to daily vibration for two weeks. The arrangement otherwise was the same as above. Serum levels of orally administered RFP were significantly decreased after a single vibration session. Repeated vibration exposure abolished the observed differences. The single vibration session had no effect on the pharmacokinetics of intravenously applied RFP.     

Oral bioavailability and pharmacokinetics of DRF-4367, a new COX-2 inhibitor in rats.

The pharmacokinetic characterization of DRF-4367 (a new diaryl pyrazole derivative), a potent selective COX-2 inhibitor was performed in Wistar rats. In the first study, a single dose of 2, 5, 10, 30 or 100 mg/kg DRF-4367 was given orally to rats for investigating the dose proportionality and/or linearity in the pharmacokinetics. In the second study, a single intravenous bolus dose of DRF-4367 was given at a dose of 10 mg/kg to calculate the absolute oral bioavailability, clearance and volume of distribution parameters. Blood samples were drawn at predetermined intervals up to 24 h post-dose. The concentrations of DRF-4367 in various plasma samples were determined by a validated HPLC method. Plasma concentration versus time data was generated following oral and i.v dosing and subjected to a noncompartmental pharmacokinetic analysis. Following oral administration, maximum concentrations of DRF-4367 were achieved at about 3 h and were unchanged with incremental doses. Both Cmax and AUC0-infinity appeared to increases less than proportional to the administered oral doses. While the doses increased in the ratio of 1.0 : 2.5 : 5.0 : 15.0 : 50.0, the mean AUC0-infinity and Cmax increased in the ratios of 1.0 : 2.8 : 4.5 : 8.6 : 14.5 and 1 : 2.4 : 4.1 : 6.2 : 8.3, respectively. Following i.v. administration, the concentration of DRF4367 declined in a monoexponential fashion with terminal elimination half-life of 5.7 h. The systemic clearance and volume of distribution of DRF-4367 in rats were 0.36 L/h/Kg and 2.2 L/Kg respectively after i.v administration. Elimination half-life was unchanged with route of administration and with increase in oral doses. Absolute oral bioavailability of DRF-4367 in the efficacy dose range was 70-80%.     

Pharmacokinetics of galantamine,a cholinesterase inhibitor,in several animal species

In this publication, single and repeated dose experiments in rats, mice, rabbits and dogs are reported to assess the pharmacokinetics of galantamine (CAS-1953-04-4), a tertiary alkaloid with reversible cholinesterase inhibiting and nicotinic receptor modulatory properties developed for the treatment of Alzheimer's disease in humans. Rats received single i.v. and single and repeated oral administrations of various doses, up to 160 mg/kg/day. In mice, only repeated oral administration of galantamine was investigated, up to 40 mg/kg/day. Galantamine single and repeated oral doses up to 32 mg/kg/day were administered to female pregnant rabbits. Beagle dogs received single i.v. and single and repeated oral administrations of doses up to 8 mg/kg/day. Generally, oral absorption was rapid, with maximal plasma levels reached within 2 h in all species. Absolute oral bioavailability of a gavage dose was high in rat (77%) and dog (78%). In mice and rats, the bioavailability of galantamine administered via the food was lower than of galantamine administered by gavage. Elimination half-life of galantamine was relatively large in rat and dog and smaller in mouse and rabbit. In general, galantamine displayed dose-proportional to somewhat more than dose-proportional kinetics. In rats, plasma levels were lower in females than in males, whereas in mice, females showed higher levels than males. No gender differences were observed in dogs. No relevant differences in exposure to galantamine were found in rats and dogs upon oral administration of galantamine obtained as a natural extract or from chemical synthesis. The exposure to the active metabolite norgalantamine in plasma of the different animal species was low, except in the dog where the steady-state norgalantamine exposure was approximately 75% of galantamine exposure. Galantamine plasma levels after single and repeated administration of 10 mg/kg/day in all species investigated except female rat and rabbit were much higher than mean therapeutic plasma levels of galantamine obtained in humans. The pharmacokinetic profile of galantamine after repeated oral administration in rats was most similar to the profile obtained after repeated administration of 12 mg b.i.d. in man.     

Six-week treatment with Ukrain in rabbits. Part II: Serum levels of gonadal hormones

The effect of 6-week treatment with Ukrain at doses of 0.3, 1.5, and 3.0 mg/kg i.v. on the serum levels of steroid hormones, i.e., estradiol, testosterone, and progesterone, was studied in rabbits of both sexes. It is demonstrated that Ukrain treatment exerts minor changes in serum hormone levels. The level of estradiol was increased in the serum of male rabbits following Ukrain treatment only at the dose of 1.5 mg/kg i.v. Similarly, the estradiol serum level was increased after Ukrain given at 1.5 mg/kg i.v. in female rabbits. In male rabbits Ukrain application at 0.3 mg/kg i.v. increased the serum testosterone level. Serum testosterone levels were not altered following Ukrain administration up to 3.0 mg/kg i.v. in female rabbits. Ukrain raised the serum progesterone levels in male rabbits at the doses of 0.3 and 3.0 mg/kg i.v. in females, only the highest dose of Ukrain produced a significant increase of serum progesterone.     

Pharmacokinetic and nephrotoxic study of gentamicin in rabbits using a new dosage regimen

Currently, in certain clinical situations there is an increasing trend towards using dosage regimens involving aminoglycoside antibiotics based on the administration of a single dose of the drug per day instead of administering the same amount in two or three administrations. The aim of the present study was to discover the pharmacokinetic profile and the nephrotoxic potential of this new form of administration in experimental animals receiving gentamicin. The study was conducted on two groups of rabbits, one of which received a single dose of the drug at 7 mg/kg i.v. and the other 7 mg/kg administered every 12 hours, allometrically equivalent to gentamicin dosing at 5 mg/kg every 24 hours to human subjects. The number of doses administered was 20. From the pharmacokinetic point of view, the results point to the existence of a significant degree of accumulation of the antibiotic in renal cortex as a result of the dosage regimen, no important modifications occurring in the pharmacokinetic parameters of gentamicin calculated from its plasma kinetics. This shows that the two compartment model employed predicts drug levels in accessible tissues but not in deep ones where gentamicin is accumulated for long periods of time. From the toxicological point of view, the treatment caused appreciable damage of the renal tubules during the first phases of the treatment which was not detectable from the serum creatinine levels or the kinetic behaviour of the aminoglycoside.     

Chemotherapeutic efficacy of nanoparticle encapsulated antitubercular drugs

Our objective was to evaluate the chemotherapeutic potential of oral poly lactide-co-glycolide (PLG, a synthetic polymer) nanoparticle encapsulated ethambutol in combination with PLG-nanoparticle encapsulated-(rifampicin + isoniazid + pyrazinamide) in a murine tuberculosis (TB) model. Our formulation was prepared by the multiple emulsion technique and administered orally to mice for the biodistribution, pharmacokinetic, and chemotherapeutic studies. A single oral administration of the formulation to mice could maintain sustained drug levels in the plasma for 5 days and in the organs (lungs, liver, spleen) for 7-9 days. There was a striking improvement in the pharmacokinetic parameters such as half-life and mean residence time as compared with free drugs. The relative/absolute bioavailability of the 4 antituberculosis drugs was enhanced several fold. Repeated administration of the formulation did not produce any hepatotoxicity as assessed on a biochemical basis. In M. tuberculosis H₃₇Rv infected mice, just 3 oral doses of the 4-drug formulation administered at every 10th day resulted in undetectable bacilli in the organs replacing 28 conventional doses of free drugs. We concluded that polymeric nanoparticle based oral 4-drug combination bears significant potential to shorten the duration of TB chemotherapy, besides reducing the dosing frequency.     

Commonly used surfactant,Tween 80, improves absorption of P-glycoprotein substrate,digoxin, in rats

Tween 80 (Polysorbate 80) is a hydrophilic nonionic surfactant commonly used as an ingredient in dosing vehicles for pre-clinical in vivo studies (e.g., pharmacokinetic studies, etc.). Tween 80 increased apical to basolateral permeability of digoxin in Caco-2 cells suggesting that Tween 80 is an in vitro inhibitor of P-gp. The overall objective of the present study was to investigate whether an inhibition of P-gp by Tween 80 can potentially influence in vivo absorption of P-gp substrates by evaluating the effect of Tween 80 on the disposition of digoxin (a model P-gp substrate with minimum metabolism) after oral administration in rats. Rats were dosed orally with digoxin (0.2 mg/kg) formulated in ethanol (40%, v/v) and saline mixture with and without Tween 80 (1 or 10%, v/v). Digoxin oral AUC increased 30 and 61% when dosed in 1% and 10% Tween 80, respectively, compared to control (P < 0.05). To further examine whether the increase in digoxin AUC after oral administration of Tween 80 is due, in part, to a systemic inhibition of digoxin excretion in addition to an inhibition of P-gp in the GI tract, a separate group of rats received digoxin intravenously (0.2 mg/kg) and Tween 80 (10% v/v) orally. No significant changes in digoxin IV AUC was noted when Tween 80 was administered orally. In conclusion, Tween 80 significantly increased digoxin AUC and Cmax after oral administration, and the increased AUC is likely to be due to an inhibition of P-gp in the gut (i.e., improved absorption). Therefore, Tween 80 is likely to improve systemic exposure of P-gp substrates after oral administration. Comparing AUC after oral administration with and without Tween 80 may be a viable strategy in evaluating whether oral absorption of P-gp substrates is potentially limited by P-gp in the gut.     

The effect of oral activated charcoal on the systemic clearance of gentamicin in rabbits with acute renal failure

The effect of oral administration of activated charcoal on total body clearance of gentamicin administered intravenously (2 mg kg-1) has been studied in normal rabbits and rabbits with induced renal failure. Gastric intubation of a single dose (10 g) of activated charcoal to normal rabbits produced a significant reduction in gentamicin serum concentrations compared to control. Significant differences between treated and control groups, compatible with enhancement of gentamicin elimination, were observed in the calculated pharmacokinetic parameters (Kel, t 1/2, CL and AUC). To examine whether renal failure could augment the effect of activated charcoal in enhancing the systemic clearance of gentamicin, uranyl nitrate was used (0.75 mg kg-1, i.v.) to induce acute renal failure in rabbits. The derived pharmacokinetic parameters of gentamicin during the control phase in these animals were consistent with severe renal failure. The administration of activated charcoal, 2.5 h following gentamicin injection, produced a steeper decline in gentamicin concentration-time profiles and significant changes in Kel, t 1/2 and CL. The Kel and CL values increased to about 200%, while the t 1/2 value decreased to about 50%. The apparent changes in the pharmacokinetic parameters induced by charcoal administration were more marked in rabbits with renal failure than in normal rabbits; however, induction of renal failure did not augment the charcoal-induced clearance of gentamicin quantitatively.     

Pharmacokinetics of Amiodarone in hyperlipidemic and simulated high fat-meal rat models

The objective of this study was to examine the effect of a high fat meal and hyperlipidemia on the pharmacokinetic behavior of amiodarone. To evaluate these effects, single doses of amiodarone were administered to rats i.v. (25 mg/kg) or orally (50 mg/kg). Some rats were rendered hyperlipidemic by intraperitoneal doses of poloxamer 407 followed by amiodarone i.v. In other normolipidemic rats, amiodarone was administered i.v. in a fasted state or after the administration of 1% cholesterol in peanut oil. Amiodarone plasma concentrations were considerably (>11-fold) increased in hyperlipidemia. Substantial decreases were noted in the clearance, volume of distribution and unbound fraction (11.6, 23 and 24.7-fold, respectively) in plasma of hyperlipidemic rats. Oral lipid caused a significant increase in plasma AUC(0-infinity) (1.38-fold) and a significant decrease in clearance (1.5-fold) of amiodarone after intravenous doses. Oral consumption of 1% cholesterol in peanut oil significantly increased the plasma AUC (1.83-fold) and bioavailability of amiodarone (1.31-fold) after oral doses. In determining oral bioavailability of lipophilic drugs such as amiodarone in food effect studies, in addition to the increase in absorption of drugs, other factors such as a decrease in clearance due to increases in lipoprotein levels should be taken into account.     

Chemotherapeutic Efficacy of Nanoparticle Encapsulated Antitubercular Drugs

Our objective was to evaluate the chemotherapeutic potential of oral poly lactide-co-glycolide (PLG, a synthetic polymer) nanoparticle encapsulated ethambutol in combination with PLG-nanoparticle encapsulated-(rifampicin + isoniazid + pyrazinamide) in a murine tuberculosis (TB) model. Our formulation was prepared by the multiple emulsion technique and administered orally to mice for the biodistribution, pharmacokinetic, and chemotherapeutic studies. A single oral administration of the formulation to mice could maintain sustained drug levels in the plasma for 5 days and in the organs (lungs, liver, spleen) for 7–9 days. There was a striking improvement in the pharmacokinetic parameters such as half-life and mean residence time as compared with free drugs. The relative/absolute bioavailability of the 4 antituberculosis drugs was enhanced several fold. Repeated administration of the formulation did not produce any hepatotoxicity as assessed on a biochemical basis. In M. tuberculosis H₃₇Rv infected mice, just 3 oral doses of the 4-drug formulation administered at every 10th day resulted in undetectable bacilli in the organs replacing 28 conventional doses of free drugs. We concluded that polymeric nanoparticle based oral 4-drug combination bears significant potential to shorten the duration of TB chemotherapy, besides reducing the dosing frequency.     

Some pharmacokinetic and pharmacodynamic interactions between digoxin and gentamicin.

Some pharmacokinetic and pharmacodynamic interactions between digoxin and gentamicin were studied in experiments on rabbits, guinea-pigs and cats. An increase of digoxin serum levels and changes in some basic pharmacokinetic parameters of digoxin (t1/2 alpha t1/2 beta, AUC, C1) were found in gentamicin-pretreated rabbits, the changes being dependent on the dose and schedule of administration. The most pronounced changes were those in digoxin kinetics during simultaneous 5-day treatment with digoxin (0.035 mg/kg i.v.) and nontoxic (10 and 2 mg/kg) doses of gentamicin. The toxicity of digoxin in guinea-pigs, assessed by administration of lethal doses of digoxin, was increased only after the highest dose of gentamicin (100 mg/kg), while after nontoxic or close to therapeutic doses (10 and 2 mg/kg) of gentamicin, the digoxin toxicity was either unchanged or even decreased. Digoxin decreased the nerve-muscle blocking effect of gentamicin on cat ischiadicus-gastrocnemius preparation. The possible mechanisms involved are discussed.     

Pharmacokinetics and absolute bioavailability of oral cefuroxime axetil in the rat

The objectives of this study were to determine the oral bioavailability of cefuroxime (C) and to evaluate the pharmacokinetic model that best describes the plasma concentration behaviour following single intravenous (IV), intraperitoneal (IP) and oral single doses. The same dose of C was administered by IV, IP and oral routes to three separate groups of rats (2.02 mg of cefuroxime axetil (CA) by the oral route or 1.78 mg of cefuroxime sodium (CNa) by IV and IP route). A two-compartment open model without lag time can predict the C disposition kinetics. The influence of the administration route on the pharmacokinetic parameters and AUC values was investigated by means of a one-way analysis of variance test. The results indicated that the first-pass effect in the intestine and liver reduce oral bioavailability when the drug is administered orally. Cefuroxime bioavailability after oral and IP administration estimated from the plasma levels was nearly 24 and 75%, respectively.     

Population pharmacokinetic approach to compare oral and i.v. administration of etoposide

The antitumor effect of etoposide (ETO) may be related to duration of exposure to a relatively low serum level while myelosuppression may be dependent on peak ETO serum levels. With regard to such therapeutic ranges, duration of exposure to predefined plasma ETO concentration ranges and the related AUC (expressed as percent of total AUC, pAUC) were used to compare pharmacokinetic profiles after oral and short time i.v. (1 h infusion) administration of identical ETO doses (100 mg/m2). Patients included in this study received i.v. (18 patients, short-term infusions) or oral (16 patients) ETO on different treatment schedules. Plasma ETO concentrations were determined by HPLC and population pharmacokinetic parameters were calculated (P-Pharm 1.4). Despite an 'apparent bioavailability' of 59%, oral administration of ETO was associated with the same time of exposure to a predefined 'therapeutic range' of 0.5-3 mg/l and a significantly higher pAUC compared to i.v. administration. By contrast, time of exposure to the probably more myelotoxic concentration range above 3 mg/l was significantly shorter and the related pAUC was highly significantly lower after oral than after i.v. administration. These findings demonstrate that oral ETO therapy is at least equivalent to short time i.v. therapy in terms of achieving specific target concentration ranges and avoiding peak concentrations.     

Species differences in the pharmacokinetics of recainam, a new anti-arrhythmic drug

The pharmacokinetics of recainam, an anti-arrhythmic drug, were compared in mice, rats, rabbits, dogs, rhesus monkeys, and man. Bioavailability was virtually complete in monkeys and dogs, 67 per cent in man and 51 per cent in rats. Non-linear kinetics between the oral and i.v. dose in rabbits precluded estimation of bioavailability. Linear plasma dose proportionality occurred in dogs between 6 and 60 mg kg-1 oral doses and rhesus monkeys between 1 and 15 mg kg-1 i.v. doses. A greater than proportional increase in the plasma AUC of recainam occurred between oral doses ranging from 54-208 mg kg-1 in mice, 25-110 mg kg-1 in rats, and 50-100 mg kg-1 in rabbits. In human subjects, the AUC/unit dose was linear between 400 and 800 mg. The terminal elimination t1/2 of recainam ranged from 1-5h in laboratory animals and man. The plasma Cmax and AUC of recainam were virtually identical after single or multiple (21 day) oral doses in dogs. After an i.v. dose, plasma clearance of recainam (l kg-1 .h) was 4.9-5.2 in rats and rabbits and 0.4-1.9 in dogs, rhesus monkeys, and man. The steady state volume of distribution was 2-5 times larger than the total body water of laboratory animals and man. Recainam was very poorly bound (10-45 per cent) to the serum proteins of rodents, rabbits, dogs, rhesus monkeys and man. In rhesus monkeys and man, recainam accounted for 10 per cent and 70 per cent, respectively, of the plasma radioactivity at 6 h post-dose. The pharmacokinetic profile of recainam in dogs most closely resembled that of man.     

Effect of oral administration of crude aqueous extract of garlic on pharmacokinetic parameters of isoniazid and rifampicin in rabbits

AIM: To study the effect of oral administration of crude aqueous extract of garlic for 14 days on pharmacokinetic parameters of isoniazid and rifampicin. MATERIALS AND METHODS: Crude extract was prepared according to the method described by Fromtling and Bulmer. The study was done on 16 New Zealand white rabbits, divided into two groups of 8 animals each for two drugs. Baseline pharmacokinetic parameters for single-dose isoniazid and rifampicin were calculated from plasma drug concentrations obtained at various time intervals after dosing. The animals were given garlic extract orally for 14 days. Pharmacokinetic parameters were calculated again as done previously. OBSERVATIONS: Administration of crude aqueous extract of garlic significantly altered the pharmacokinetic parameters for isoniazid. C(max) was reduced from 15.4 +/- 5.6 to 5.4 +/- 3.3 microg/ml. AUC((0-24)) was reduced from 76.7 +/- 25.0 to 34.3 +/- 19.2 microg/ml.h. No significant change in T(max), k(el) and AUC((0-)(alpha)) was seen. Pharmacokinetic parameters of rifampicin were not significantly altered by administration of garlic extract. CONCLUSIONS: Oral administration of garlic extract decreased the bioavailability of isoniazid significantly with no change in rate of elimination. Bioavailability of rifampicin is not significantly altered by garlic extract.