Renal excretion of intravenously infused amoxycillin and ampicillin.

The aim of this study was to determine whether concentration-dependent renal clearance of ampicillin and amoxycillin occurs. The drugs were given as single 20 min i.v. infusions in doses ranging from 1.9 to 2.8 g to nine healthy volunteers using a cross-over design. Plasma and urinary concentrations were determined by a selective liquid chromatographic method using frequent sampling up to 10 and 30 h respectively after termination of the infusion. The renal clearance of the drugs was independent of the plasma concentration. The mean (s.d.) renal clearances of ampicillin and amoxycillin were 167 (24) and 157 (20) ml min-1 1.73 m-2 respectively. The net secretion was about 50% of the total renal clearance of both drugs. The plasma concentration and urinary excretion rate versus time curves indicated a polyexponential decline, which could be described by both a biexponential and a triexponential equation. The former proved to be more reliable, especially in the calculation of micro rate constants. There was a tendency to more sustained plasma concentrations after amoxycillin, also illustrated by a significantly lower mean (s.d.) plasma clearance of this drug, viz. 185 (30) ml min-1 1.73 m-2, as compared to ampicillin, 210 (24) ml min-1 1.73 m-2 (P less than 0.04). There were no major differences in the disposition rate constants and the distribution volumes of ampicillin and amoxycillin. The mean (s.d.) plasma half-life was 1.7 (0.3) h for both drugs. The urinary excretion rate indicated a slower terminal disposition rate however, with ampicillin and amoxycillin half-lives of 3.4 (2.0) and 3.9 (1.2) h respectively. The longer half-life in the terminal phase may be due to increased tubular reabsorption at low urinary concentrations. It was not possible to determine in this study whether the half-life was affected by changes in clearance or volume of distribution. The urinary solubility of the drugs was dependent on pH. This could explain the massive macroscopic crystalluria seen in one subject after amoxycillin. Three hours after termination of the infusion, crystals could no longer be found in the sediment. There was no clinical or laboratory evidence of renal damage.     

Pharmacokinetics of ampicillin and its prodrugs bacampicillin and pivampicillin in man

Five healthy fasting male subjects were each given single doses of intravenous ampicillin (471 mg), oral ampicillin tablets (495 mg), oral bacampicillin hydrochloride tablets (562 mg ampicillin equivalent), and oral pivampicillin hydrochloride capsules (491) mg ampicillin equivalent) in a crossover experiment. The resulting concentrations of ampicillin were determined in plasma and urine. The pharmacokinetic analysis was made according to a two-compartment open model. The total distribution volume of unbound ampicillin during the disposition phase was 0.247 +/- 0.045 (SD) liter/kg, which is only slightly more than the extracellular fluid, suggesting that tissue binding and intracellular distribution of ampicillin are limited. The bioavailability of the esters bacampicillin (86 +/- 11%) and pivampicillin (92 +/- 18%) was significantly greater than that of ampicillin (62 +/- 17%); however, the difference between the esters was not statistically significant. The adsorption for all drugs given orally proceeded at a constant rate, suggesting zero-order release rates from the products. The adsorption rate was highest for bacampicillin (0.89 +/- 0.39 of dose absorbed per minute), followed by pivampicillin (0.64 +/- 0.19) and ampicillin (0.58 +/- 0.16). Bacampicillin also had the shortest lag time for the start of absorption (7.0 +/- 0.9 min) under the present conditions. Thus, in comparison with ampicillin, the esters have a higher bioavailability, which, in fact, is close to the theoretically highest possible value by clearance concepts. The higher bioavailability in connection with higher absorption rates may be clinically important in ampicillin treatment by the oral route.     

Bacampicillin Hydrochloride: Chemistry,Pharmacology, and Clinical Use

Bacampicillin hydrochloride is an orally administered ester of ampicillin that is rapidly and completely hydrolyzed in vivo to ampicillin. The most notable advantage of bacampicillin over ampicillin is its superior bioavailability — bacampicillin achieves significantly higher blood and tissue levels and attains peak blood levels more rapidly than equimolar doses of oral ampicillin. In addition, the percentage of an oral dose of ampicillin that is absorbed decreases sharply as the size of the dose is increased from 500 mg to 2 g; this phenomenon is not observed with equipotent doses of bacampicillin. The enhanced absorption of bacampicillin in the upper gastrointestinal tract results in a frequency of diarrhea that appears to be markedly lower than that of ampicillin and similar to that observed with amoxicillin. Apart from the sizable differences between bacampicillin and ampicillin with regard to oral absorption, the pharmacokinetic and pharmacologic profiles of these two agents are essentially identical. Twice daily dosing (pulse dosing) with bacampicillin has been shown in numerous clinical trials to be of equivalent efficacy to ampicillin given four times daily or amoxicillin given three times daily in the treatment of infections of the upper respiratory tract, lower respiratory tract, skin and soft tissues, and urinary tract. The unanswered question is whether twice daily ampicillin or amoxicillin would yield similar results.     

Intra- and inter-individual variation in pharmacokinetics of intravenously infused amoxycillin and ampicillin to elderly volunteers.

The purpose of this study was to investigate the disposition of two aminopenicillins and their intra- and inter-individual variation in pharmacokinetic parameters in healthy, elderly volunteers. Two groups, each of 12 active, community-dwelling volunteers between 69 and 83 years of age participated. One group was given 500 mg of amoxycillin, the other group 500 mg of ampicillin as single i.v. infusions. Within the drug groups each volunteer was given the infusion at two different occasions separated by a time-period of 1 week. Amoxycillin and ampicillin were determined in plasma and urine by modern column liquid chromatographic methods. The mean plasma clearance was about 200 ml min-1 1.73 m-2 for both drugs and renal clearance accounted for approximately 80% of this. As expected, drug clearance was correlated to renal function as determined by 51Cr-EDTA. The volume of distribution at steady-state (Vss) was about 0.3 l kg-1 for both drugs. Compared to our previous results in younger subjects, plasma and renal clearances were essentially similar in this study, but slightly longer half-lives and higher Vss were seen for amoxycillin and ampicillin. The intra-individual variation, expressed as the error of a single determination (CV), was small, for plasma clearance 3.7% and 6.4% after amoxycillin and ampicillin. The corresponding inter-individual variation in clearance was higher, 14.4% after amoxycillin, and 11.9% after ampicillin. The results confirm a higher relative efficiency of a crossover vs a completely randomized parallel groups design in parenteral studies of these penicillins. In our elderly subjects there was only an approximately 30% decrease in renal function. This was not enough to reduce the drug clearance and offers an explanation for the similarity between our present results in the elderly and our previous results in younger subjects. Elderly volunteers may be different from patients with disease as a confounding factor. Studies on elderly active and community-dwelling volunteers, as in this study, may therefore be more representative as to the effect of age per se on drug kinetics.     

Pharmacokinetics of ampicillin and its prodrugs bacampicillin and pivampicillin in man

Five healthy fasting male subjects were each given single doses of intravenous ampicillin (471 mg), oral ampicillin tablets (495 mg), oral bacampicillin hydrochloride tablets (562 mg ampicillin equivalent), and oral pivampicillin hydrochloride capsules (491 mg ampicillin equivalent) in a crossover experiment. The resulting concentrations of ampicillin were determined in plasma and urine. The pharmacokinetic analysis was made according to a two-compartment open model. The total distribution volume of unbound ampicillin during the disposition phase was 0.247 ± 0.045 (sd) liter/kg, which is only slightly more than the extracellular fluid, suggesting that tissue binding and intracellular distribution of ampicillin are limited. The bioavailability of the esters bacampicillin (86 ± 11%) and pivampicillin (92± 18%) was significantly greater than that of ampicillin (62 ± 17%); however, the difference between the esters was not statistically significant. The absorption for all drugs given orally proceeded at a constant rate, suggesting zero-order release rates from the products. The absorption rate was highest for bacampicillin (0.89 ± 0.39% of dose absorbed per minute), followed by pivampicillin (0.64 ± 0.19) and ampicillin (0.58 ± 0.16). Bacampicillin also had the shortest lag time for the start of absorption (7.0 ± 0.9 min) under the present conditions. Thus, in comparison with ampicillin, the esters have a higher bioavailability, which, in fact, is close to the theoretically highest possible value by clearance concepts. The higher bioavailability in connection with higher absorption rates may be clinically important in ampicillin treatment by the oral route.This work was supported by the Swedish Medical Research Council, Project No. 522 (L. O. B.).     

The effect of sudanese food and chloroquine on the bioavailability of ampicillin from bacampicillin tablets

The effect of Sudanese food and chloroquine on the bioavailability of ampicillin from bacampicillin was investigated. The bioavailability of ampicillin was determined using the urinary excretion method. The urinary levels of ampicillin were measured chemically. Bacampicillin capsules were administered: (i) under different dietary conditions; and (ii) on an empty stomach together with chloroquine phosphate tablets. Unlike the case of ampicillin capsules, neither food nor chloroquine affected the bioavailability of ampicillin from bacampicillin capsules. The difference between ampicillin and bacampicillin capsules with respect to the effect of food and chloroquine on ampicillin bioavailability is discussed.     

The Influence of Uptake from the Gastrointestinal Tract and First-pass Effect on Oral Bioavailability of (Z)-alkyloxyimino Penicillins

We have investigated the contribution of uptake from the gastrointestinal tract and first-pass effect to the poor oral bioavailability of a series of (Z) -alkyloxyimino penicillins in mice. Investigative studies in gut sacs and perfused small intestine demonstrated that these penicillins were able to pass across the mucosal epithelium although to a lesser extent than amoxycillin and cyclacillin, both of which exhibit excellent oral bioavailability in man and animals. In the jejunal gut sacs the mucosal to serosal flux for BRL 44154 was approximately half that of amoxycillin and four times less than that of cyclacillin, and for all, uptake was pH dependent. The serosal to mucosal fluxes were however similar for these compounds and significantly lower than mucosal to serosal fluxes, suggesting involvement of carrier mechanisms in uptake from the mucosal surface. The order of results for the alkyloxyimino penicillins paralleled that observed for oral bioavailability in the mouse. For the alkyloxyimino penicillins, between 5·5 and 9·9% was taken up from the perfused intestine, values which were significantly less than those for amoxycillin (13·2%) and cyclacillin (33·3%). However, uptake was concentration-dependent for BRL 44154 as it was for amoxycillin, thus confirming the possible use of carrier mechanisms in absorption. These observations suggest that the poor peripheral blood concentrations of the alkyloxyimino penicillins achieved after oral dosing were not a consequence of the inability of the compounds to cross the mucosal epithelium. The biliary clearance of the alkyloxyimino penicillins was, however, considerably greater than for amoxycillin and cyclacillin, a finding which may well have been a contributory factor to the comparatively low peripheral concentrations of BRL 44154 and its analogues achieved after oral administration.     

Determination of dose-dependent absorption of amoxycillin from urinary excretion data in healthy subjects.

Measurement of unchanged drug in urine was used to study the rate and extent of amoxycillin absorption after administration of amoxycillin sodium solution to six healthy subjects in a Latin-Square crossover design. The mean (95% CI) fraction of the dose excreted as unchanged amoxycillin decreased (P < 0.05) from 0.50 (0.44-0.56) after 97 mg amoxycillin sodium (= 0.25 mmol amoxycillin) to 0.23 (0.19-0.27) after 3103 mg (8 mmol), while the mean residence time determined from urinary excretion rate data increased (P < 0.05) from 1.54 (1.32-1.76) h to 2.16 (2.01-2.41) h. Plots of total urinary excretion and initial (0-30 min) excretion of unchanged drug vs dose indicated significant non-linearity above 776 mg doses. Michaelis-Menten parameters describing this relationship with respect to amount absorbed were 3.02 mmol for maximum amount absorbed and 1.93 mmol for amount absorbed at half maximum for 0-30 min. These results support a saturable absorption mechanism for amoxycillin which had clinical implications for high oral amoxycillin doses, and for competition with other drugs having capacity-limited absorption.     

Influence of hyperthyroidism on the kinetics of methimazole,propranolol, metoprolol and atenolol

Summary The kinetic profiles of oral methimazole 40mg, propranolol 80mg, metoprolol 100mg and atenolol 100mg were compared in hyperthyroid patients both during the hyper-and euthyroid states. For methimazole, neither the peak concentration (C_max), the time to reach peak concentration (t_max), the elimination half-life (t_1/2) nor the area under the curve (AUC) value was affected by the hyperthyroid state. For propranolol and metoprolol, which undergo extensive presystemic clearance, the AUC values were lower (p<0.02) when the patients were hyperthyroid than when they had become euthyroid, but the t_1/2's were not significantly altered. For atenolol, there were no significant kinetic differences between the hyperthyroid and euthyroid states. The findings are compatible with the assumption that hyperthyroidism does not affect the kinetics of methimazole or atenolol, but that it may enhance presystemic clearance of propranolol and metoprolol.     

Assessment of glibenclamide pharmacokinetics in poloxamer 407-induced hyperlipidemic rats

The aim of the present research was to describe the consequences of hyperlipidemia (HL) on the pharmacokinetics of glibenclamide (Gb) in poloxamer 407-induced hyperlipidemic rats. Rats were given intraperitoneal dose of poloxamer 407 to cause hyperlipidemia. A single oral dose of Gb (10 mg/Kg) was given to normal and HL rats. The C_max and t_max after oral dose of Gb in normal rats were 340.10 µg/ml and 3.67 h, respectively. Whereas, the C_max and t_max after oral dose of Gb in HL rats were noted as 773.39 µg/ml and 2.50 h respectively. The AUC value of Gb was found considerably higher in the HL rats. While the plasma clearance (CL) after oral dose of Gb was 2.53 ml/h and 1.39 ml/h in normal and HL rats respectively. The improved plasma concentration of Gb following oral dosing in rats with HL seems to be due to a direct influence on hepatic clearance or metabolizing enzymes. In conclusion, the Gb pharmacokinetics was considerably affected by the HL in rats. Such findings play an important role for predicting the alterations in the pharmacokinetics of drugs including GB, in cases having hyperlipidemia.     

Sultamicillin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use

Sultamicillin is the tosylate salt of the double ester of sulbactam plus ampicillin. Sulbactam is a semisynthetic beta-lactamase inhibitor which, in combination with ampicillin, extends the antibacterial activity of the latter to include some beta-lactamase-producing strains of bacteria that would otherwise be resistant. The combination of sulbactam plus ampicillin for parenteral use has previously been shown to be clinically and bacteriologically effective in a variety of infections. The chemical linkage of sulbactam and ampicillin has now produced an orally effective compound, sultamicillin, with antibacterial activity and clinical efficacy which are similar to those of the parenteral formulation. Sultamicillin has been shown to be clinically effective in non-comparative trials in patients with infections of the respiratory tract, ears, nose and throat, urinary tract, skin and soft tissues, as well as in obstetric and gynaecological infections, and in the treatment of gonorrhoea. In a small number of controlled trials, sultamicillin has shown comparable clinical efficacy to phenoxymethyl penicillin (penicillin V) and to amoxycillin (alone and in combination with clavulanic acid) in the treatment of paediatric streptococcal pharyngitis and acute otitis media, respectively; to cefaclor in the treatment of acute otitis media in adults; and to bacampicillin, cloxacillin and flucloxacillin plus ampicillin in skin and soft tissue infections in adults, children and adult diabetic patients, respectively. Sultamicillin was superior in efficacy to bacampicillin in the treatment of chronic respiratory infections, to cefaclor in the treatment of acute otitis media in adults, and to cefadroxil in the treatment of patients with complicated urinary tract infections. However, in single-dose treatment of uncomplicated gonorrhoea, sultamicillin (1500mg plus probenecid 1g) was inferior to a 2g intramuscular dose of spectinomycin. While in several studies the incidence of diarrhoea associated with sultamicillin was greater than that with comparative antibacterials, sultamicillin-associated diarrhoea was generally mild and transitory, although occasionally severe enough to necessitate discontinuation of treatment. Further studies in larger groups of patients are needed to clarify the therapeutic efficacy and safety of sultamicillin in comparison with other antibacterial regimens, and to determine the optimum single dosage for the treatment of gonorrhoea. Nonetheless, sultamicillin appears to provide a similar pharmacodynamic and pharmacokinetic profile to that of parenteral sulbactam plus ampicillin and, as such, will extend the therapeutic efficacy of ampicillin, with the further advantage of allowing treatment of patients with an oral formulation, thus avoiding the potentially adverse clinical and financial effects of prolonged parenteral therapy.     

Correlation between the bioavailability of microencapsulated bacampicillin hydrochloride in suspension and in vitro microcapsule dissolution

The relative bioavailability of microencapsulated bacampicillin hydrochloride in suspension was correlated with the in vitro dissolution half-lives of the microcapsules. Simultaneously, a sensory evaluation was performed to evaluate the taste acceptability of the suspension. The in vitro dissolution half-life is directly related to the coating thickness of the microcapsules. The four suspensions of bacampicillin hydrochloride, containing microcapsules with different coating thickness, were given as single 400-mg oral doses to 12 healthy volunteers after overnight fasting using a crossover design with balanced sequences. Bacampicillin is a prodrug of ampicillin, the concentration of which was determined in plasma and urine by bioassay. There were significant inverse linear relationships between the dissolution half-life and plasma peak concentration, area under the curve, and urinary recovery. The terminal exponential disposition phases of the curves were similar for all four suspensions. There was a significant direct linear relationship between the dissolution half-life and overall taste and bitterness. The results show that the mean bioavailability of bacampicillin hydrochloride from a microcapsule suspension can be predicted from an in vitro dissolution half-life. The results also suggest that bacampicillin hydrochloride can be given in a suspension with sufficient microcapsule film thickness to reduce the bitter taste of the drug and still retain adequate bioavailability.     

Pharmacokinetics of temocapril,an ACE inhibitor with preferential biliary excretion,in patients with impaired liver function

Summary Six subjects with normal liver function (Group 1) and 7 patients with liver dysfunction (Group 2; mean ICG_R15 value 30.5 (5.2) %; range 16 to 56) received a single oral dose of 1 mg temocapril, a prodrug-type ACE inhibitor, with preferentially excreted by the biliary route.The plasma temocapril concentrations in Group 2 at 30 min and 1 h postdose were significantly higher than in Group 1, but the difference had disappeared 2 h postdosing. Although the half life of temocapril diacid in Group 2 was significantly longer than in Group 1, there was no significant difference between the two groups in AUC, C_max or t_max. In Group 2, urinary recovery of temocapril was significantly increased, suggesting a possible delay in the bioactivation of temocapril into the diacid, but recovery of the diacid itself was not abnormal. ACE inhibitory action in Group 2 remained unchanged.Temocapril is regarded as an ACE inhibitor the disposition and efficacy of which are little affected in patients with impaired liver function.     

Amoxycillin injectable: a review of its antibacterial spectrum, pharmacokinetics and therapeutic use.

Amoxycillin, an acid stable semisynthetic penicillin shown to be effective against a wide range of infections when given orally, is now available for intramuscular and intravenous injection. Amoxycillin has an antibacterial spectrum and level of activity essentially the same as for ampicillin. Amoxycillin has been shown to have more rapid and complete bactericidal action than ampicillin against E. coli in vitro and in animal models of infection, but the clinical importance of this difference has not yet been determined. Amoxycillin is present in therapeutic amounts in the cerebrospinal fluid of meningitis patients given the drug intravenously and parenteral amoxycillin has been successfully used in the treatment of meningitis, and in urinary tract infections, septicaemia, upper and lower respiratory tract infections and a variety of other infections caused by Gram-negative and Gram-positive aerobic bacteria. However, the extent of experience is limited compared with ampicillin, and thus further studies are needed to more clearly delineate its relative therapeutic role. Parenteral amoxycillin is generally well tolerated. Pain at the site of intramuscular injection occurs in about one-third of patients, but can be minimised by the use of lignocaine or procaine hydrochloride.     

Effects of Long-Term Oral Carvedilol on the Steady-State Pharmacokinetics of Oral Digoxin in Patients With Mild to Moderate Hypertension

The effect of multiple oral doses of carvedilol on steady-state plasma digoxin pharmacokinetics was evaluated in 12 patients with mild to moderate hypertension. Area under the curve (AUC), mean maximum plasma concentration (C_max), mean time to maximum concentration (T_max), concentration at 24 hours after the dose (C₂₄), creatinine clearance, renal digoxin clearance, and urinary digoxin excretion were determined after patients took oral digoxin 0.25 mg once/day for 2 weeks. Carvedilol was added to the regimen, and digoxin pharmacokinetics were assessed after 2 weeks of concurrent treatment. The AUC and C_max for digoxin increased by 14% and 32%, respectively (p<0.05), with no change in T_max. The 24-hour urinary digoxin excretion and 24-hour renal digoxin clearance increased by 45% and 26%, respectively (p<0.05), with no change in creatinine clearance. Carvedilol appears to increase digoxin's oral bioavailability as well as renal elimination. The absolute change in digoxin pharmacokinetics was small and not clinically significant. The significance of the interaction in other patient populations remains to be studied.     

Single and multiple dose pharmacokinetics of enteric coated ketoprofen: Effect of cimetidine

Summary The effect of cimetidine on the single and multiple dose pharmacokinetics of enteric coated ketoprofen was studied in 12 healthy volunteers. Each subject completed two 8-day study treatment periods: either ketoprofen alone (100 mg p.o. twice daily), or co-administered with cimetidine (600 mg twice daily). t_lag, C_max, t_max, t_1/2, and k for ketoprofen were not significantly different between single and multiple dose administration. AUC of ketoprofen was slightly but significantly larger following multiple (21.2 µg·h·ml^–1) as compared to single dose administration (19.0 µg·h· ml^–1). As a result, plasma clearance of ketoprofen was slightly but significantly reduced following multiple dose administration (80.6 ml/min vs 89.3 ml/min). Cimetidine had no effect on the single or multiple dose pharmacokinetics of enteric coated ketoprofen. Total 12-h urinary recovery of ketoprofen (mostly in the form of ketoprofen glucuronide) was 83.5% of the dose following single dose administration and was significantly greater following multiple dose administration (93.1%). Again cimetidine co-administration had no effect on the single and multiple dose urinary recovery.The results of this study show that cimetidine is not affecting the oral pharmacokinetics of enteric coated ketoprofen.     

Rifampicin Treatment Greatly Increases the Apparent Oral Clearance of Qninidine

Abstract We investigated the effect of cytochrome P450 induction by rifampicin on the in vivo oxidative metabolism of quinidine. The pharmacokinetics of a 200 mg oral single dose quinidine were studied before and after one week of daily treatment with 600 mg rifampicin in six healthy young male volunteers. Biomarker reactions of cytochrome P450 isozyme activities in the form of caffeine, sparteine, mephenytoin, tolbutamide and cortisol metabolism were applied. The median total apparent oral clearance and partial clearance by 3-hydroxylation of quinidine increased 9 times. The partial clearance by N-oxidation increased 6 times. The C_max and the elimination half life were reduced 3 times. No statistically significant changes were found for quinidine t_max and renal clearance. The cortisol metabolic ratio increased 5 times, while no statistically significant effects were seen for other CYP marker reactions. The results indicate that the inductive effect of rifampicin is likely to be of clinical relevance particulary when used concomitantly with drugs metabolized by CYP3A4.     

Pharmacokinetics of Pirazolac – a New Anti-Inflammatory Drug – in Human Volunteers II. Dose Linearity of Plasma Levels and Excretion

The concentration-time course of pirazolac in plasma and its urinary excretion were investigated in 6 young volunteers (3 males, 3 females) after oral administration of 50, 150, 300, 450, and 600 mg pirazolac as a crystalline suspension at weekly intervals. Only unchanged pirazolac was detected in the plasma. Maximum plasma levels and areas under the plasma level curve increased linearly with the dose. All other pharmacokinetic parameters such as t_max (3 h), oral clearance CL (0.3ml/min/kg) and terminal plasma half life t_1/2 (16–18 h) were independent of the dose. A total of 65 % of the dose was renally excreted within 72 hours mainly as pirazolac glucuronide.     

Physicochemical properties of amphoteric beta-lactam antibiotics I: Stability, solubility, and dissolution behavior of amino penicillins as a function of pH.

The degradation rate, solubility, and dissolution rate of amino penicillins, amoxicillin, ampicillin, epicillin, and cyclacillin, were determined quantitatively as a function of pH. In the pH range studied, 0.30-10.50, the degradation of amoxicillin and epicillin followed pseudo-first-order kinetics to give the same type of pH-rate profiles as those of ampicillin and cyclacillin. Cyclacillin anhydrate was the most soluble, followed in order by ampicillin anhydrate, ampicillin trihydrate, amoxicillin trihydrate, and epicillin anhydrate. These pH-solubility profiles showed showed U-shaped curves. The dissolution rate constants from the rotating disk were analyzed by the simultaneous chemical reaction and diffusion models. Their relative bioavailability after a single oral administration was assessed from their physicochemical properties determined in vitro.     

Dose Proportionality and Population Characteristics of Oral Fadrozole Hydrochloride,an Aromatase Inhibitor,in Postmenopausal Women

The dose proportionality of the pharmacokinetics of fadrozole was investigated in 18 healthy postmenopausal women. Fadrozole hydrochloride was administered as 0.3-, 1.0-, and 2.0-mg oral doses continuously every 12 hr for 5 days each in a Latin square design. At steady state, the dose-normalized pharmacokinetic parameters AUC and C _max were found to be independent of the dose. In addition, no statistically significant differences in t _max were detected. It was concluded that the pharmacokinetics of fadrozole were dose proportional in the projected therapeutic dose range. The relationship between oral clearance and the demographic factors, age, weight, and height, was assessed. Oral clearance was related to total body weight but not age or height. Prospective estimates of the population components of variance showed that intersubject variance accounted for 91.7% of the total random variance. Weight variance accounted for 36.1% of the intersubject variance.