Pharmacokinetic interaction of megestrol acetate with zidovudine in human immunodeficiency virus-infected patients.

This nonrandomized, two-period crossover study was performed to assess whether concomitant administration of megestrol acetate influences the steady-state pharmacokinetics of zidovudine and its inactive 5'-O-glucuronide metabolite. Twelve HIV-positive, asymptomatic male volunteers received a 100-mg oral capsule dose of zidovudine at least 30 min before meals five times a day at 0700, 1100, 1500, 1900, and 2300 h on study days 1 to 3 and a single 100-mg dose at 0700 h on day 4. On days 5 to 17, 800 mg of megestrol acetate, as a 40-mg/ml aqueous suspension, was administered orally immediately before the 0700 h dose of zidovudine. On days 5 to 16, zidovudine was also administered at 1100, 1500, 1900, and 2300 h. Serial blood samples were collected for 12 h after the single 100-mg dose of zidovudine on days 4 and 17; trough samples were also obtained just before the 0700 h dose on days 2 to 4 and 15 to 17. Levels of zidovudine and its glucuronide in plasma were assayed by a validated radioimmunoassay. Statistical analysis of trough plasma level data indicated that steady-state levels of zidovudine and its glucuronide in plasma had been attained when pharmacokinetic assessments were made on days 4 and 17. When megestrol acetate and zidovudine were coadministered for 13 days, differences of -14, -6.5, and -4.6% in mean zidovudine peak concentration and areas under the curve at 0 to 4 and 0 to 12 h, respectively, +22.5% in mean trough concentration, +2.6% in mean plasma half-life, and no change in median time to peak were observed compared to conditions when zidovudine was administered alone; for zidovudine 5'-O-glucuronide the respective differences were -9, -7.3, -4.4, +2.3, and +10% and no change. None of the differences were statistically significant (P > 0.05). Concomitant therapy with megestrol acetate, at the dose employed to treat anorexia, cachexia, or an unexplained, significant weight loss in AIDS patients, did not alter the steady-state pharmacokinetics of zidovudine or its 5'-O-glucuronide metabolite.

Single-dose and steady-state pharmacokinetics of fosinopril and fosinoprilat in patients with hepatic impairment.

The single-dose and steady-state pharmacokinetics of the angiotensin-converting enzyme (ACE) inhibitor fosinopril and its active diacid, fosinoprilat, were evaluated in 6 healthy volunteers and 12 patients with alcoholic cirrhosis. Fosinopril was administered at a dosage of 10 mg once daily for 14 days. Results in the two groups were similar, with no evidence of accumulation of fosinoprilat in hepatically impaired patients. Mean (+/- SD) maximum observed plasma concentrations of fosinoprilat in the healthy subjects were 112.0 +/- 67.2 ng/mL after the first dose and 144.1 +/- 61.7 ng/mL at steady-state. Corresponding values for the hepatically impaired patients were 111.4 +/- 40.1 ng/mL and 140.2 +/- 50.9 ng/mL. The area under the serum concentration versus time curve for healthy volunteers was 790.7 +/- 431.0 ng.hr/mL after the first dose and 940.3 +/- 400.4 ng.hr/mL at steady-state. Similar values were noted in hepatically impaired patients: 926.0 +/- 293.9 ng.hr/mL and 1,255.4 +/- 434.0 ng.hr/mL for first dose and steady-state, respectively. No statistically significant differences were detected in fosinoprilat pharmacokinetic values between healthy and hepatically impaired subjects. Absence of accumulation can be attributed to the dual route of elimination of fosinoprilat reported in previous studies. Renal excretion of fosinoprilat in hepatically impaired patients prevents increased accumulation. The present findings suggest that the starting dose of fosinopril used in hypertensive patients with normal renal and hepatic function can also be used in patients with hepatic impairment secondary to cirrhosis.

A study of pharmacokinetic interaction between buspirone and alprazolam at steady state.

The steady-state pharmacokinetic interaction between buspirone and alprazolam was evaluated in a parallel study with two groups of 12 male volunteers each. On days 1 to 7, group I subjects received a 1-mg alprazolam tablet every 8 hours (q8h) (TRT 1) and group II subjects received 2 x 5-mg buspirone tablets q8h (TRT 2). On days 8 through 14, all subjects received a combination of 1-mg alprazolam and 2 x 5-mg buspirone tablets q8h (TRT 3). Plasma samples, collected 0 to 8 hours after the morning dose on days 7 and 14, were analyzed for buspirone, alprazolam and their metabolites, 1-PP, and alpha-HO-alprazolam, respectively. Additional samples were collected before the morning dose on days 5 and 6 of each session to monitor the attainment of steady state. Steady-state pharmacokinetic parameters Cmax, Tmax, AUC0-8, and Cmin were calculated. The results indicated that for alprazolam, there was a small (< 10%) increase in Cmax and AUC when coadministered with buspirone. For buspirone, there was a 10% and 29% increase in Cmax and AUC, when coadministered with alprazolam. These values were within the normal variability observed with this class of drugs. Except for a 14% decrease in Cmin for alpha-HO-alprazolam, coadministration of buspirone and alprazolam did not affect the parameters for the metabolites. The results of this study suggest that coadministration of buspirone and alprazolam did not markedly affect the steady-state pharmacokinetics of either drug.

Pharmacokinetics of mitomycin C in dogs: application of a high-performance liquid chromatographic assay.

A normal-phase high-performance liquid chromatographic (HPLC) assay was developed for the determination of mitomycin C in plasma and urine. The method involves extraction of mitomycin C from plasma or urine into ethyl acetate-2-propanol-chloroform (70:15:15) with UV detection at 365 nm. Quantitation was performed with an internal standard (porfiromycin) by the peak height ratio method. Excellent correlation was obtained between the HPLC assay and the established microbiological cup-plate bioassay. The pharmacokinetics of mitomycin C were investigated in beagle dogs following a 1-mg/kg iv (22-mg/m2) bolus dose. The plasma mitomycin C concentration versus time data were analyzed by using an open three-compartment model. The average volume of distribution was 1.90 L or 17% of body weight for the central compartment and 7.7 L or 68% of body weight for the terminal elimination phase. The volumes of distribution at steady state, calculated by model-dependent and -independent methods, compared very well with each other and were 6.5 L or 58% of body weight. Total body clearance averaged 112 mL/min, and the mean terminal plasma half-life was 53 min. The 0-24-h urinary excretion of intact mitomycin C accounted for 19% of the dose. The terminal half-life and percent urinary recovery of mitomycin C in dogs is similar to that in humans. Based on these observations, the dog appears to be a good model for studying the disposition of mitomycin C.

Evaluation of the bioavailability of sarpicillin, the methoxymethyl ester of hetacillin, in humans.

The relative bioavailability of sarpicillin (the methoxymethyl ester of hetacillin) from three different oral dosage forms was compared in humans employing a three-way crossover study design. Each unit dose contained 250 mg of sarpicillin in terms of anhydrous ampicillin activity. The comparative bioavailability of a tablet containing added buffer, a liquid-filled capsule, and a standard powder-filled capsule was determined. The bioavailability parameters were Cmax, tmax, and AUC of intact plasma sarpicillin levels and saliva ampicillin levels. Significant correlation was found between plasma sarpicillin levels and saliva ampicillin levels following the administration of sarpicillin. All three formulations yielded statistically similar Cmax and AUC values with respect to plasma sarpicillin and saliva ampicillin levels. However, a more rapid absorption of intact sarpicillin was observed with the buffered tablet formulation, as reflected by significantly smaller tmax for both plasma sarpicillin and saliva ampicillin levels. The faster absorption from the tablet formulation gave more precise absorption among subjects.

Pharmacokinetics of intramuscular ceforanide in infants, children, and adolescents.

We studied the pharmacokinetics of intramuscular ceforanide in 46 infants, children, and adolescents, ranging in age from 1 month to 17 years. After the subjects were given 20-mg doses of ceforanide per kg, the mean peak plasma concentration was 56.3 microgram/ml (range, 27.0 to 95.0), the mean 8-h level was 5.9 microgram/ml (range, 1.5 to 13.5), and the mean 12-h level was 1.5 microgram/ml (range, 0.2 to 4.2). Ceforanide half-life varied with the ages of the patients: in 1- to 2-year-old children, in half-life was significantly shorter (1.5 h) than in younger or older children. Plasma concentrations at 8 and 12 h after a dose were lowest in 1- to 2-year-old children. There was no relationship between the area under the curve, the volume of distribution, or the body clearance of ceforanide to the ages of the patients. Within 6 h of administration of the drug, a mean of 77.5% of a dose was excreted in urine, and at the end of 12 h, virtually all (93.9%) of the administered dose was recovered in urine samples. The administration of ceforanide every 12 h did not result in drug accumulation. A dose of 20 mg of ceforanide per kg every 12 h is recommended for most pediatric patients. Dosage recommendations for 1- to 2 year-old children are presented.

Human pharmacokinetics and disposition of sarmoxicillin, a lipophilic amoxicillin prodrug.

Sarmoxicillin, an amoxicillin prodrug, is the methoxymethyl ester of hetamoxicillin. Esterification converted amoxicillin from an amphoteric to a cationic compound and resulted in a 30- to 600-fold increase in lipid partitioning. Oral absorption studies in normal subjects demonstrated that sarmoxicillin was only partially hydrolyzed by nonenzymatic and gut or hepatic first-pass metabolism and that significant quantities of intact ester appeared in the systemic circulation. Sarmoxicillin was converted to amoxicillin in plasma by hydrolysis of the acetone penicinate and the methoxymethyl ester bonds. Significant amoxicillin levels were demonstrated in saliva after administration of sarmoxicillin, but not amoxicillin, over a 250- to 1,000-mg dose range. Differences in the absorption, distribution, or metabolism of amoxicillin were also evident in the lower plasma amoxicillin maximum concentration and area under the curve and longer half-life after sarmoxicillin administration. Differences in the distribution of this lipophilic ester could result in a significant increase in tissue penetration and subsequent therapeutic efficacy of amoxicillin when administered as sarmoxicillin.

Effect of dosing volume on intramuscular absorption rate of aminoglycosides.

The Loo-Riegelman method was applied to serum amikacin level data after intravenous and intramuscular administration. Intramuscular amikacin absorption can be described by first-order kinetics, but the absorption rate constant decreased from 1.95 hr-1 at a 125-mg dose to 1.00 hr-1 at a 750-mg dose. This rate change apparently is a physical phenomenon due to differing dosing volumes at different doses and attendant changes in the surface area to volume ratio at the injection site. Amikacin absorption rates on intramuscular injection can be maximized by giving several smaller injections rather than a single larger injection. This phenomenon should be generally observed with aminoglycoside antibiotics and could be partly responsible for reported variations in the absorption rate and the poor predictability of serum concentrations.

Comparative tissue distribution of ceforanide, cefazolin, and cefamandole in rats.

The comparative tissue distribution of ceforanide, cefazolin, and cefamandole was determined in rats after subcutaneous doses of 100 mg/kg. Ceforanide had the longest plasma half-life, 0.9 h, versus 0.5 h for cefazolin and 0.4 h for cefamandole, and the highest area under the plasma concentration time curve, 324 micrograms x h per ml, versus 184 micrograms x h per ml for cefazolin and 42 micrograms x h per ml for cefamandole. The peak plasma concentrations of ceforanide and cefazolin were 173 and 140 micrograms/ml, respectively, and were threefold higher than that of cefamandole (49 micrograms/ml). Measureable concentrations of the three compounds were found in the liver, kidneys, lungs, submaxillary glands, cervical lymph nodes, bones, heart, abdominal muscles, eyes, and testes, with cefamandole levels being generally lower and more variable. The peak tissue levels of ceforanide and cefazolin were comparable, within the limit of data variation, and were considerably higher than that of cefamandole. The tissue half-lives of these cephalosporins were similar to the respective plasma half-lives.

Preliminary studies of the pharmacokinetics of talisomycin in the rhesus monkey.

The single dose intravenous pharmacokinetics of talisomycin (3 mg/M2) and bleomycin (18 U/M2) were determined in the rhesus monkey at non-nephrotoxic doses. Serum concentrations were analyzed by radioimmunoassay procedures. The tissue distribution of talisomycin was significantly higher and the elimination slower than bleomycin. The volume of distribution (Vdss) was 2.3 and 22.6 L/M2 for bleomycin and talisomycin, respectively. The volume of the peripheral tissue compartment (V2) of talisomycin was 17 times greater than bleomycin. The slower elimination of talisomycin was reflected by a half-life (t1/2) of 10.6 hr versus 1.6 hr for bleomycin. The slower elimination from the peripheral tissue compartments was also evidenced by a five-fold difference in the tissue transfer ratio (k12/k21) for these compounds. Similar differences, of lesser magnitude, have also been reported in the dog. The potential for higher tissue distribution and slower elimination of talisomycin could be related to the differences in in vivo antitumor activity and toxicity, and should be considered in design of the dose schedule in clinical studies.

Bioavailability and metabolism of potassium phosphanilate in laboratory animals and humans.

Phosphanilic acid is an antibacterial agent with a mode of action and antibacterial spectrum similar to those of sulfamethoxazole, with the exception that it has potent antipseudomonal activity. Bioavailability studies in rats (50, 300, and 600 mg/kg, oral and subcutaneous), dogs (50, 150, and 450 mg/kg, oral and intravenous infusion), and humans (400 and 800 mg, oral) showed that the extent of oral absorption of potassium phosphanilate was low. The bioavailability, calculated by comparing the oral values for area under the plasma concentration curve with those for the respective parenteral doses, was 10% for rats and 45 (50 and 150 mg/kg) and 19% (450 mg/kg) for dogs. The 24-h urinary recovery also confirmed the low oral bioavailability, i.e., rat, 13 (oral) and 75% (subcutaneous); dog, 15 to 29 (oral) and 87% (intravenous) of the dose. Plasma levels and urinary recovery (4%, oral) were low and variable in humans. The poor absorption of oral doses may be due to drug precipitation in the stomach, low permeability of the soluble species due to extensive in situ ionization (pK(a), 1.8 to 2) in the intestine, or first-pass metabolism to N-acetylphosphanilic acid. The plasma t((1/2)) values after parenteral administration were 0.3 h in rats and 1.3 h in dogs. Although the lack of adequate blood levels of phosphanilic acid after oral administration in humans precludes the use of this compound for treatment of systemic infections, the sustained urinary concentration at levels severalfold higher than the minimal inhibitory concentration (1 mug/ml) for at least 10 h postdose was indicative of the therapeutic usefulness in urinary tract infections.

Disposition of parenteral butorphanol in man.

The metabolism and elimination of 3H-butorphanol (levo-3, 14-dihydroxy-N-(cyclobutylmethyl)[15-3H]morhinan) tartrate were determined in man after therapeutic im (2 mg) and iv (1 mg) doses. As judged from urinary excretion of radioactivity, the im dose was completely absorbed. Butorphanol was rapidly distributed to tissues, had a plasma half-life of about 3 hr, and was extensively metabolized prior to elimination. The major route of elimination was renal, with fecal excretion being a minor route. Hydroxybutorphanol [3, 14-dihydroxy-N-(trans-3'-hydroxycyclobutylmethyl)morphinan] was isolated and identified as a major urinary metabolite and was also present in the plasma. The disposition of butorphanol is compared and contrasted to the disposition of morphine and pentazocine.

Human pharmacokinetics of a new braod-spectrum parenteral cephalosporin antibiotic, ceforanide.

The pharmacokinetics of the l-lysine salt of ceforanide were studied after intravenous administration of 1132 and 2264 mg as 30-min constant-rate infusions and after intramuscular administration of 556 and 1132 mg. The peak intravenous plasma concentrations were 136 and 222 microgram/ml at termination of infusion, and 12-hr trough concentrations were 5.9 and 9.0 microgram/ml, respectively. The peak intramuscular plasma concentrations were 38 and 74 microgram/ml at 1.0-1.3 hr after dosing, and 12-hr trough concentrations were 3.9 and 6.7 microgram/ml, respectively. When 19 successive intravenous and intramuscular doses at these levels were administered at 12-hr intervals, there was no tendency toward drug accumulation. The major drug elimination route was urinary excretion; 85% of the dose was excreted unchanged in the urine within 12 hr, and no metabolites with antibiotic activity were observed in urine. The mean terminal plasma half-life was 2.98 hr, the mean plasma protein binding was 80.6%, the steady-state volume of distribution was 12 liters, the plasma clearance was 45.9 ml/min/1.73 m2, and the renal clearance was 34.9 ml/min/1.73 m2. The pharmacokinetic properties and antibacterial activity spectrum indicate that this antibiotic should be effective in treating human bacterial infections when administered at 12-hr intervals. It is presently under clinical investigation.

Comparative pharmacokinetics of ceforanide (BL-S786R) and cefazolin in laboratory animals and humans.

Ceforanide (BL-S786R) is a new, broad-spectrum, parenteral cephalosporin. Pharmacokinetic properties were determined in rats (100 mg/kg), rabbits (30 mg/kg), dogs (25 mg/kg), and humans (2 g or 30 mg/kg) and compared with equivalent single doses of cefazolin. Plasma half-lives for ceforanide and cefazolin were 1.1 and 0.5 h in the rat, 5 and 0.3 h in the rabbit, 1 and 0.8 h in the dog, and 2.6 and 2 h in humans, respectively. The slower elimination of ceforanide, as reflected by longer plasma half-life, larger area under the curve, and peak plasma concentrations, was due to slower body and renal clearances. The apparent volumes of distribution of ceforanide and cefazolin were comparable. Rats, dogs, and humans excreted 80 to 100% of the ceforanide dose in the 0- to 24-h urine; rabbits excreted only 50%. Tubular secretion constituted 50% of ceforanide renal excretion in rabbits, dogs, and humans and 90% in rats; the remainder was excreted by glomerular filtration. There was no apparent correlation between the extent of tubular secretion and degree of plasma protein binding in different species. There was no significant pharmacokinetic interaction between ceforanide and amikacin in the rat. The slower elimination kinetics of ceforanide are indicative of the potential for a longer dosing interval and more effective antibiotic therapy as compared with available cephalosporins.

Clinical pharmacokinetics and safety of high doses of ceforanide (BL-S786R) and cefazolin.

The pharmacokinetics and safety of ceforanide and cefazolin were compared in normal subjects after 30-min intravenous infusions of 2-, 3-, and 4-g single doses and 4-g twice-daily doses for 10 days. No significant differences were observed in plasma-renal pharmacokinetic parameters between single and multiple doses of ceforanide. Half-life (t((1/2)), 2.8 h), plasma clearance (Cl(p), 48 ml/min per 1.73 m(2)), and renal clearance (Cl(0-12h) (r), 47 ml/min per 1.73 m(2); tubular secretion, 44%, and glomerular filtration, 56%) did not change with increased dose or on multiple dosing. No significant change was observed in t((1/2)) (1.9 h), area under the plasma concentration-time curve, Cl(r) (60 ml/min per 1.73 m(2); tubular secretion, 80%, and glomerular filtration, 20%), or Cl(p) (75 ml/min per 1.73 m(2)) for 4-g single doses compared with twice-daily administration of cefazolin. A small increase in cefazolin clearance was observed when plasma concentrations were greater than 100 mug/ml, when the single dose was increased from 2 to 4 g; this was a result of the decrease in percentage of plasma protein binding and increased renal clearance due to increased glomerular filtration. The increase in renal clearance resulted in a lack of linear proportionality of the plasma area under the curve with dose over a range of 2 to 4 for both cephalosporins, although this effect was much less marked with ceforanide. Both compounds were well tolerated both locally and systemically. There was no evidence of any change in renal function based on clearances of drug, p-aminohippuric acid, or creatinine, and other standard clinical parameters.

Comparative pharmacokinetics and metabolism of cephapirin in laboratory animals and humans.

Comparative drug disposition studies in mice, rats, dogs, and humans indicate that cephapirin, a new semisynthetic cephalosporin antibiotic that exhibits broad-spectrum antimicrobial activity, is metabolized to desacetylcephapirin in these species. Pharmacokinetic analyses of the concentrations of cephapirin and desacetylcephapirin in plasma and urine reveal that the rate and extent of deacetylation decreases from rodents to dogs to humans. The kinetic analyses also suggest that the kidney performs a role not only in the excretion but also in the metabolism of cephapirin to desacetylcephapirin.