Pharmacokinetics, oral bioavailability, and metabolic disposition in rats of (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine, a nucleoside analog active against human immunodeficiency virus and hepatitis B virus.

The pharmacokinetics and metabolism of the potent anti-human immunodeficiency virus and anti-hepatitis B virus compound, (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine (FTC), were investigated in male CD rats. Plasma clearance of 10 mg of FTC per kg of body weight was biexponential in rats, with a half-life at alpha phase of 4.7 +/- 1.1 min (mean +/- standard deviation) and a half-life at beta phase of 44 +/- 8.8 min (n = 5). The total body clearance of FTC was 1.8 +/- 0.1 liters/h/kg, and the oral bioavailability was 90% +/- 8%. The volume of distribution at steady state (Vss) was 1.5 +/- 0.1 liters/kg. Increasing the dose to 100 mg/kg slowed clearance to 1.5 +/- 0.2 liters/kg/h, lowered the Vss to 1.2 +/- 0.2 liters/kg, and reduced the oral bioavailability to 65% +/- 15%. FTC in the brains of rats was initially less than 2% of the plasma concentration but increased to 6% by 2 h postdose. Probenecid elevated levels of FTC in plasma as well as in brains but did not alter the brain-to-plasma ratio. The urinary and fecal recoveries of unchanged FTC after a 10-mg/kg intravenous dose were 87% +/- 3% and 5% +/- 1.6%, respectively. After a 10-mg/kg oral dose, respective urinary and fecal recoveries were 70% +/- 2.5% and 25% +/- 1.6%. Two sulfoxides of FTC were observed in the urine, accounting for 0.4% +/- 0.03% and 2.7% +/- 0.2% of the intravenous dose and 0.4% +/- 0.06% and 2.5% +/- 0.3% of the oral dose. Also observed were 5-fluorocytosine, representing 0.4% +/- 0.06% of the intravenous dose and 0.4% +/- 0.07% of the oral dose, and FTC glucuronide, representing 0.7% +/- 0.2% of the oral dose and 0.4% +/- 0.2% of the intravenous dose. Neither deaminated FTC nor 5-fluorouracil was observed in the urine (less than 0.2% of dose). The high oral availability and minimal metabolism of FTC encourage its further preclinical development.     

Pharmacokinetics, oral bioavailability, and metabolism in mice and cynomolgus monkeys of (2'R,5'S-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine, an agent active against human immunodeficiency virus and human hepatitis B virus.

(2'R,5'S-)-cis-5-Fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine (524W91) is a nucleoside analog with potent anti-human immunodeficiency virus and anti-human hepatitis B virus activities in vitro. The pharmacokinetics and bioavailability of 524W91 after oral dosing were studied in mice dosed with 10, 100, and 600 mg of 524W91 per kg of body weight by the oral and intravenous routes. Cynomolgus monkeys were dosed with 10 and 80 mg of 524W91 per kg. In both species, the clearance of 524W91 was rapid, via the kidney, and was independent of dose. In monkeys, the total body clearance of 10 mg of 524W91 per kg was 0.7 +/- 0.1 liter/h/kg, and the volume of distribution at steady state was 0.8 +/- 0.02 liter/kg. The terminal elimination half-life was 1.0 +/- 0.2 h. The absolute bioavailability after oral dosing was 63% +/- 4% at 10 mg/kg. Concentrations of 524W91 in the cerebrospinal fluid were 4% +/- 0.7% of the corresponding levels in plasma. In mice, the total clearance of 10 mg of 524W91 per kg was 2.3 liters/kg/h, and the volume of distribution at steady state was 0.9 liter/kg. Absolute bioavailability in mice after oral dosing was 96% at a dose of 10 mg/kg. The metabolism of orally administered [6-3H]524W91 was studied in cynomolgus monkeys at a dose of 80 mg/kg and in mice at a dose of 120 mg/kg. Monkeys excreted 41% +/- 6% of the radioactive dose in the 0- to 72-h urine, 33% +/- 10% in the feces, and 10% +/- 7% in the cage wash. Unchanged 524W91 was 64% of the total radiolabeled drug recovered in the urine. The glucuronide was a minor urinary metabolite. 5-Fluorouracil was not detected (less than 0.02% of the dose). Mice dosed orally with 120 mg of [6-3H]524W91 per kg excreted 67% +/- 7% of the radiolable in the )- to 48-h urine. Small amounts of the 3' -sulfoxide and glucuronide metabolites were observed in the urine, but 5-fluorouracil was not detected. Good bioavailability after oral dosing and resistance to metabolism recommend 524W91 for further preclinical evaluation.     

Kinetics of fenoximone, a new cardiotonic, in healthy subjects

Fenoximone, a new cardiotonic, was given to six healthy men as a single intravenous dose of 1 mg/kg and a single oral dose of 3 mg/kg as solution in a crossover study. Plasma concentrations were monitored for 8 hr and urine was collected for 24 hr. Peak plasma concentrations (Cmax) were reached 30 min after the oral dose. Decay of plasma concentrations was fitted to a mean (+/- SD) elimination t1/2 (t1/2 beta) of 60 +/- 14 min after intravenous injection and 78 +/- 26 min after oral dosing. Mean total body clearance for intravenous dosing was 2062 +/- 846 ml/min, renal clearance (ClR) was 5.3 +/- 2.4 ml/min, and extrapolated volume of distribution was 0.37 +/- 0.26 l/kg. The sulfoxide derivative was detected as the main metabolite. Cmax of the sulfoxide metabolite occurred 10 min after the end of the intravenous infusion and 20 to 60 min after oral dosing. From the decay of the plasma concentrations of the sulfoxide, the t1/2 beta s were calculated as 132 +/- 15 min after intravenous injection and 140 +/- 27 min after oral dosing of fenoximone. ClR of the sulfoxide was 499 +/- 106 ml/min after intravenous injection; 24-hr urinary recovery of the sulfoxide was 75.7% +/- 5.7% after intravenous injection and 64.3% +/- 10.4% after oral dosing. Mean oral bioavailability of fenoximone was 53% (range 44% to 69%).     

Pharmacokinetics of beta-L-2',3'-dideoxy-5-fluorocytidine in rhesus monkeys

beta-L-2',3'-Dideoxy-5-fluorocytidine (beta-L-FddC), a novel cytidine analog with an unnatural beta-L sugar configuration, has been demonstrated by our group and others to exhibit highly selective in vitro activity against human immunodeficiency virus types 1 and 2 and hepatitis B virus. This encouraging in vitro antiviral activity prompted us to assess its pharmacokinetics in rhesus monkeys. Three monkeys were administered an intravenous dose of [3H] beta-L-FddC at 5 mg/kg of body weight. Following a 3-month washout period, an equivalent oral dose was administered. Plasma and urine samples were collected at various times for up to 24 h after dosing, and drug levels were quantitated by high-pressure liquid chromatography. Pharmacokinetic parameters were obtained on the basis of a two-compartment open model with a first-order elimination from the central compartment. After intravenous administration, the mean peak concentration in plasma (Cmax) was 29.8 +/- 10.5 microM. Total clearance, steady-state volume of distribution, terminal-phase plasma half-life (t1/2 beta), and mean residence time were 0.7 +/- 0.1 liters/h/kg, 1.3 +/- 0.1 liters/kg, 1.8 +/- 0.2 h, and 1.9 +/- 0.2 h, respectively. Approximately 47% +/- 16% of the intravenously administered radioactivity was recovered in the urine as the unchanged drug with no apparent metabolites. beta-L-FddC exhibited a Cmax of 3.2 microM after oral administration, with a time to peak drug concentration of approximately 1.5 h and a t1/2 of 2.2 h. One monkey in the oral administration arm of the study had a significant delay in the absorption of the aqueous administered dose. The absolute bioavailability of orally administered beta-L-FddC ranged from 56 to 66%.     

Ribavirin disposition in high-risk patients for acquired immunodeficiency syndrome

Ribavirin is a broad-spectrum antiviral drug that has in vitro activity against human immunodeficiency virus. To determine the kinetics of ribavirin, 17 symptom-free homosexual men with lymphadenopathy were studied. Single doses of ribavirin, 600, 1200, or 2400 mg, were given orally or intravenously. The plasma ribavirin concentration-time profiles were well fitted by a three-compartment open model. Ribavirin followed linear kinetics over the dose range studied. The mean 1-hour postinfusion concentrations after intravenous ribavirin, 600, 1200, and 2400 mg, were 8.0, 19.7, and 37.1 mumol/L, respectively. The mean +/- SD plasma beta-phase half-life, terminal-phase (gamma) half-life, and volume of distribution at steady state were 2.0 +/- 1.1 hours, 35.5 +/- 14.0 hours, and 647 +/- 258 L, respectively. The mean ribavirin renal clearance and total body clearance were 99 +/- 30 and 283 +/- 37 ml/min, respectively. After an oral dose of 600, 1200, and 2400 mg, the mean peak plasma ribavirin concentrations (which occurred 1.5 hours after administration) were 5.1, 9.9, and 12.6 mumol/L, respectively. The mean absorption half-life and bioavailability of ribavirin were 0.5 hour and 45%. Ribavirin had no plasma protein binding and the drug accumulated within red blood cells. In conclusion, ribavirin is incompletely absorbed from the gastrointestinal tract, its renal excretion accounts for approximately one third of the drug's elimination, and drug accumulation (greater than threefold) will result with repetitive dosing at the 6- to 8-hour dosing interval currently used.     

Pharmacokinetics of KRM-1648, a new benzoxazinorifamycin, in rats and dogs.

The pharmacokinetics of 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl) benzoxazinorifamycin (KRM-1648) in rats and dogs given a single oral dose of 3, 30, or 100 mg/kg of body weight were studied. In the rats, the concentrations of KRM-1648 in plasma, whole blood, and tissues peaked between 2.0 and 24.0 h, with elimination half-lives ranging from 6.2 to 19.5 h. The peak concentrations and the areas under the concentration-versus-time curves (AUC) for whole blood and tissues were 2 to 277 times higher than those for plasma. The high levels of KRM-1648 in tissues were consistent with its large volume of distribution (in excess of 10 liters/kg). A nonlinear increase in peak concentrations and AUCs for plasma, whole blood, and tissues occurred as the dose was increased and was consistent with the dose-dependent decrease in bioavailability. In the dogs, KRM-1648 levels in plasma and whole blood also exhibited a late time to the peak concentration (ranging from 4.0 to 11.2 h), a long elimination half-life (ranging from 15.2 to 24.0 h), and nonlinear kinetics. KRM-1648 exhibited high levels of plasma protein binding (more than 99%) and a high degree of affinity for lipoproteins in the plasma of both animals. After administration of KRM-1648, measurable levels of its metabolites, 25-deacetyl KRM-1648 in rats and 25-deacetyl KRM-1648 and 30-hydroxy KRM-1648 in dogs, were found in the biological samples tested. Thus, KRM-1648 is characterized by a high tissue affinity, a long elimination half-life, and nonlinear pharmacokinetics.     

Pharmacokinetics and clinical tolerance of intravenous and oral cyclosporine in the immediate postoperative period

The clinical tolerance and pharmacokinetics of cyclosporine during a prolonged intermittent intravenous infusion (3.5 mg/kg/day three times) followed by an 8 mg/kg daily oral dose was evaluated in eight renal transplant recipients in the immediate postoperative period. Cyclosporine was analyzed from whole blood samples by HPLC. Despite peak drug concentrations of 1463 +/- 754 ng/ml during the infusion period, no adverse pulmonary effects were noted; renal function, urine output, and mean arterial pressure also appeared to have been unaffected. The mean trough cyclosporine concentration was 141 +/- 50 ng/ml; however, two patients had trough values below sensitivity. Kinetic analysis after the third dose of intravenous cyclosporine revealed a mean total body clearance of 0.31 +/- 0.1 L/min and a volume of distribution of 2.88 +/- 1.1 L/kg, whereas the elimination half-life was 12.8 +/- 3.8 hours and the mean residence time was 9.5 +/- 5.1 hours. After conversion to oral therapy the bioavailability ranged from 0.11 to 0.47, with a mean value of 0.27. Subsequently there was an unpredictable pattern of bioavailability within patients, with mean values of 0.27 +/- 0.13 and 0.30 +/- 0.25 during the second and third oral study periods, respectively. These data suggest that despite adjusting the intravenous cyclosporine dosage to account for acute changes in patient body weight, variable kinetics may result in subtherapeutic trough values, even when cyclosporine is administered by prolonged infusion. The clinical implications of fluctuating cyclosporine bioavailability and a potential alternative approach to dosing are discussed.     

Pharmacokinetics and antiviral activity in simian varicella virus-infected monkeys of (R,S)-9-[4-hydroxy-2-(hydroxymethyl) butyl]guanine, an anti-varicella-zoster virus drug.

The acyclic guanosine analog (R,S)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine, (+/-)2HM-HBG, is an effective inhibitor of herpes simplex virus and varicella-zoster virus infections in vitro. This report is concerned with the pharmacokinetic evaluation of the drug in rats and monkeys and its antiviral activity in African green monkeys infected with simian varicella virus (SVV), a virus closely related to varicella-zoster virus that is also susceptible to inhibition by (+/-)2HM-HBG. Elimination half-lives in plasma following intravenous administration to monkeys (100 mumol/kg of body weight) ranged from 1.8 to 2.2 h, and total body clearance was 9.0 +/- 0.4 ml/min per kg (mean +/- standard error). After oral administration, levels in plasma were low, with a maximum concentration of the drug of only 3.1 +/- 0.8 microM, a time to reach maximum concentration of drug of 2.7 +/- 0.4 h, and an oral bioavailability of 10.6 +/- 1.4%. Because of the low oral bioavailability, SVV-infected monkeys were treated intramuscularly with (+/-)2HM-HBG. (+/-)2HM-HBG at a dosage of 10 mg/kg of body weight per day allowed moderate viremia, whereas a dosage of 30 mg/kg of body weight per day strongly suppressed viremia with minimal numbers of virus plaques from blood specimens collected at days 3, 5, and 7 postinfection and complete clearance at day 9 postinfection. Titers of antibody to SVV were also low. Treatment three times daily was somewhat more efficacious than treatment twice daily. Thus, (+/-)2HM-HBG is an effective inhibitor of SVV replication in vivo, despite the fact that leves of (+/-)2HM-HBG in plasma were low at extended periods of time and below the concentration of drug giving 50% inhibition of plaque formation obtained in vitro.     

Didanosine pharmacokinetics in patients with normal and impaired renal function: influence of hemodialysis.

The pharmacokinetics of didanosine were investigated following oral administration of a single 375-mg dose to eight human immunodeficiency virus-seropositive patients with normal renal function and eight human immunodeficiency virus-seropositive uremic patients. In uremic patients, the plasma half-life was longer than that in control patients (respectively, 4.5 +/- 2.2 and 1.6 +/- 0.4 h). The ratio of total plasma clearance to absolute bioavailability was four- to fivefold lower in uremic patients than in patients with normal renal function (respectively, 491 +/- 181 and 2,277 +/- 738 ml/min). Because of the decrease in elimination, concentrations in plasma were higher for uremic patients than for control patients; the maximum concentrations of drug in plasma were, respectively, 3,978 +/- 1,607 and 1,948 +/- 994 ng/ml; the areas under the concentration-time curve were, respectively, 14,050 +/- 4,262 and 3,000 +/- 956 ng.h/ml. Didanosine was removed by hemodialysis with an extraction ratio of 53% +/- 8%, a hemodialysis clearance value of 107 +/- 21 ml/min, and a fractional drug removal during a 4-h dialysis of 20% +/- 8% of the dose. Dosage adjustments are necessary in uremic patients.     

Absorption,pharmacokinetics and excretion of levovirin in rats,dogs and cynomolgus monkeys

The absorption, pharmacokinetics and excretion of levovirin were studied in Sprague-Dawley rats (30 mg/kg) and Beagle dogs (30 mg/kg) following intravenous (iv) and oral administration of [(3)H]levovirin, and in Cynomolgus monkeys following iv and oral administration of [(14)C]levovirin. Oral absorption was 31.3% in rats, 67.3% in dogs and 17.5% in monkeys, and the bioavailability was 29.3% in rats, 51.3% in dogs and 18.4% in monkeys. After iv administration, the elimination half-life (t(1/2)) was 1.47 h in rats, 3.70 h in dogs and 3.50 h in monkeys. The total body clearance was 8.24, 2.96 and 2.58 mL/min per kg, respectively, in rats, dogs and monkeys and the apparent volume of distribution was 0.79, 0.95 and 0.65 L/kg. No metabolite was detected in plasma or urine of rats, dogs or monkeys, indicating negligible metabolism of levovirin in these animals. Excretion of total radioactivity in urine after oral dosing accounted for 15.4% of the administered dose in rats, 49.9% in dogs and 21.4% in monkeys. Biliary excretion did not play a significant role in the elimination of levovirin.     

Preclinical pharmacokinetics and distribution to tissue of AG1343, an inhibitor of human immunodeficiency virus type 1 protease.

AG1343, a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) protease (Ki = 2 nM), was designed by protein structure-based drug design techniques. AG1343 has potent antiviral activity (95% effective dose = 0.04 microgram/ml) against a number of HIV-1 strains in acute and chronic models of infection. As part of its preclinical development, the oral bioavailability of AG1343 in rats, dogs, monkeys, and marmosets was determined and its tissue distribution in rats was evaluated. There were no major interspecies differences in AG1343 pharmacokinetics. Following intravenous administration, the elimination half-life of AG1343 ranged from 1 to 1.4 hr. The total volume of distribution (2 to 7 liters/kg) exceeded the volume of total body water, indicating extensive tissue distribution. Systemic clearance of AG1343 (1 to 4 liters/kg) in the different species corresponded to hepatic blood flow, suggesting possible hepatic involvement in the elimination of AG1343. Following oral administration, peak levels in plasma ranged from 0.34 microgram/ml after treatment with 10 mg/kg of body weight in the dog to 1.7 micrograms/ml after dosing with 50 mg/kg in the rat. Because of the slow absorption of AG1343, plasma concentrations of AG1343 exceeding that required for 95% inhibition of HIV-1 replication were maintained for up to 7 h after a single oral dose in all species evaluated. Average oral bioavailability of AG1343 ranged from 17% in the marmoset to 47% in the dog. Studies of distribution to tissue in the rat after oral administration of 14C-AG1343 established extensive distribution with concentrations in most tissues exceeding that found in plasma. Of particular significance were high levels of AG1343 equivalent in mesenteric lymph nodes (32.05 micrograms/g) and spleen tissue (9.33 micrograms/g). The major excretory route for AG1343 was via feces, with 100% of the dose recovered by 48 h. Results from these studies demonstrate that AG1343 is orally bioavailable and that levels in plasma in the therapeutic range are achievable and are maintained for prolonged periods in the animal models tested. On the basis of these and other findings, AG1343 was developed for further testing in human subjects.     

Pharmacokinetics of a water-soluble fullerene in rats.

Fullerenes are the recently discovered third allotropic form of carbon. The biological activities of these compounds are being studied for various purposes. The bis(monosuccinimide) derivative of p p'-bis(2-amino-ethyl)-diphenyl-C60 (MSAD-C60) is a water-soluble fullerene derivative. MSAD-C60 has been shown to have antiviral activity against human immunodeficiency virus types 1 and 2 in vitro and to have virucidal and anti-human immunodeficiency virus protease activities. Moreover, MSAD-C60 has been shown to be well tolerated in mice after intraperitoneal administration. The purpose of the present study was to develop a high-performance liquid chromatographic analytical methodology for MSAD-C60 and to characterize the preclinical pharmacokinetics of the compound in rats. Following intravenous administration of the fullerene derivative at a dose of 15 mg/kg of body weight, the concentrations of MSAD-C60 in plasma declined either bi- or triexponentially. The mean terminal-phase half-life of MSAD-C60 was 6.8 +/- 1.1 h (mean +/- standard deviation). Binding studies indicated that the compound is greater than 99% bound to plasma proteins. The average total clearance of the compound was 0.19 +/- 0.06 liter/h/kg. Urine samples obtained 24 h after intravenous administration did not contain detectable levels of the compound, indicating the absence of a significant renal clearance mechanism. The steady-state volume of distribution of MSAD-C60 averaged 2.1 +/- 0.8 liters/kg, indicating that the compound distributes into tissues. At a dose of 15 mg/kg, MSAD-C60 appeared to be well tolerated. However, a dose of 25 mg/kg resulted in shortness of breath and violent movement of the rats, followed by death within 5 min of dosing. Further controlled toxicity studies are needed to fully evaluate the toxicity of the compound.     

Pharmacokinetics of the oral triazole antimycotic vibunazole in animals

Methods of assay of the oral triazole antimycotic vibunazole (BAY n 7133) in body fluids by GLC, HPTLC and by a microbiological assay are described and compared. Bioassay data of vibunazole concentrations in mice and rats are lower than those of the chemical methods, probably due to a species-dependent difference in protein binding. The pharmacokinetics of vibunazole was studied after administration to mice, rats, rabbits, beagle dogs and rhesus monkeys. Peak concentrations of 14 to 16 mg/l were found in plasma of mice after oral administration of 25 mg/kg as an aqueous suspension. After the first oral dose the mean plasma half-life was 4.8 h. After the fifth dose, plasma levels were lower and declined with a half-life of 1.2 h which may indicate enzyme induction. Signs of enzyme induction after multiple oral doses were also seen in beagle dogs but not in rhesus monkeys. After intravenous administration to one beagle dog, vibunazole plasma half-life was 1.8 h. The absolute bioavailability of oral vibunazole in the dog was estimated to be about 70%.     

Oral melphalan kinetics.

The systemic availability of melphalan after oral administration is not well known. Most patients are put on a fixed oral dosage regimen. We have studied the disposition of melphalan in 14 patients after single oral doses. Five were also studied after receiving the same dose intravenously. Oral melphalan had a mean plasma terminal phase half-life (t1/2) of 90 +/- 17 min. The mean area under the plasma concentration:time curve (CXT) was 53 +/- 33 micrograms . min/ml. Urinary excretion of oral melphalan averaged 10.9 +/- 4.9% during the first 24 hr. The CXT ratio (oral:intravenous) for the 5 patients studied after both oral and intravenous melphalal (0.6 mg/kg) ranged between 0.25 and 0.89 and averaged 0.56. After oral dosing in 14 fasting patients, the time at which melphalan first appeared in the plasma varied between 15 min and 6 hr. In a myeloma patient who took oral melphalan, no melphalan was found in plasma or urine up to 24 hr. Some instances of failure of tumor response to oral melphalan may be due to inadequate bioavailability rather than inherent tumor resistance.     

Pharmacokinetics of dapsone in human immunodeficiency virus-infected children.

Dapsone, administered at various doses and schedules, has been proven to be a safe and effective alternative to trimethoprim-sulfamethoxazole for prevention of Pneumocystis carinii pneumonia (PCP) in adults with human immunodeficiency virus (HIV) infection. Dapsone is also recommended by the Centers for Disease Control for PCP prophylaxis in HIV-infected children. However, the suggested dosage regimen is based upon clinical experience with children with leprosy and dermatitis herpetiformis rather than pharmacokinetic and pharmacodynamic data obtained from the target patient population. In order to determine a rational dosage regimen that could be tested in clinical studies aimed at the evaluation of dapsone for the prevention of PCP in HIV-infected children, we studied the pharmacokinetics of dapsone following a 2-mg/kg of body weight oral dose in twelve HIV-positive children aged 9 months to 9 years. Plasma was collected at the following times after dapsone administration: 0, 2, 4, 6, 12, 24, 48, 72, and 96 h. The levels of dapsone in plasma were determined by high-performance liquid chromatography. Data were analyzed by noncompartmental methods. Expressed as means +/- standard deviations (ranges), the pharmacokinetic parameters were as follows: peak concentration in plasma, 1.12 +/- 0.48 (0.44 to 1.81) mg/liter; time to peak concentration in plasma, 3.8 +/- 1.3 (2 to 6) h; half-life at elimination phase, 24.2 +/- 7.1 (14.4 to 35.0) h; clearance from plasma divided by bioavailability (CL/F), 1.15 +/- 0.67 (0.37 to 2.63) ml/min/kg; and volume of distribution divided by bioavailability (V/F), 2.25 +/- 1.20 (1.00 to 4.57) liters/kg. Oral CL correlated negatively with age (r = 0.614 and P = 0.034), as did V (r = 0.631 and P = 0.028). As a consequence of the high interindividual variability in growth retardation, pharmacokinetic parameters correlated with measures of body development better than they did with age (e.g., for CL/F to height, r = 0.765 and P = 0.004, and for V/F to height, r = 0.748 and P = 0.005). Since oral CL from plasma and V were positively and highly correlated (r = 0.898 and P = 0.0001), a lower absolute F may be the cause, in part, of higher values for CL/F and V/F in smaller children. The results of this study warrant the testing of a 2-mg/kg dose of dapsone administered twice or thrice weekly to HIV-infected children. The monitoring of drug levels in plasma and dosage adjustment may be necessary for smaller children.     

Nizatidine disposition in subjects with normal and impaired renal function

To test the hypothesis that renal insufficiency alters nizatidine disposition, we determined the pharmacokinetics of nizatidine and its major metabolite after a single oral dose in normal volunteers and patients with various degrees of renal dysfunction, after a single intravenous dose in normal volunteers and patients with severe renal failure and during hemodialysis. After intravenous administration the elimination half-life increased from 1.5 +/- 0.2 hours in normal volunteers to 6.9 +/- 3.3 hours in patients with renal failure. The plasma clearance decreased from 0.59 +/- 0.07 L/kg/hr in normal volunteers to 0.14 +/- 0.02 L/kg/hr in patients with renal failure. Nizatidine bioavailability was nearly 100% in normal volunteers but decreased to 75% in patients with renal failure. The volume of distribution was 1.3 +/- 0.1 L/kg in normal volunteers and was not different in patients with renal failure. Nizatidine protein binding was about 30% in normal and uremic plasma. The drug was not substantially removed by hemodialysis. Patients with creatinine clearances less than 50 ml/min/1.73 m2 should receive 150 mg nizatidine once each evening. Patients with creatinine clearances less than 20 ml/min/1.73 m2 should receive 150 mg nizatidine every other night.     

Clinical pharmacologic observations on atenolol, a beta-adrenoceptor blocker.

The effects of oral and intravenous administration of atenolol were studied in healthy volunteers. The oral administration of a series of single doses of atenolol reduced an exercise tachycardia. After a 200-mg dose, the effect on an exercise tachycardia was maximal at 3 hr and declined linearly with time at a rate of approximately 10% per 24 hr. The peak plasma atenolol concentration occurred at 3 hr and thereafter declined exponentially with time with an elimination half-life of 6.36 +/- 0.55 hr: 43 +/- 3.9% of the dose was excreted in the urine within 72 hr. There was a correlation between the reduction in an exercise tachycardia and the logarithm of the corresponding plasma concentration. The intravenous administration of atenolol reduced exercise tachycardia with a significant correlation between effect and plasma concentration. After 50 mg intravenously, 100% of the dose was recovered from the urine, and the clearance was 97.3 ml/min. Comparison of AUC O leads to chi after oral and intravenous administration of 50 mg showed the bioavailability to be 63% after oral drug. Repeated oral administration of atenolol 200 mg daily either as a single dose or in divided 12 hourly doses for 8 days maintained reduction of an exercise tachycardia of at least 24% during the period of drug administration. The plasma elimination half-life, area under the plasma concentration-time curve, and peak plasma concentration after 200 mg atenolol were not changed by chronic dosing for 8 days.     

Pharmacokinetics of rifabutin.

We investigated the pharmacokinetics of rifabutin in 15 male patients as part of a phase I trial of the treatment of early symptomatic human immunodeficiency virus infection. Six or more patients were studied at each of four different oral dosage levels: 300, 600, 900, and 1,200 mg/day. Twelve studies were also conducted with tracer doses of intravenous radiolabeled [14C]rifabutin. Blood and urine samples were collected for at least 72 h after the first (day 1) and last (day 28) doses of rifabutin and analyzed by high-pressure liquid chromatography. The plasma concentration data were best described by a two-compartment open model with a terminal half-life of 36 h. Rifabutin was rapidly absorbed, reaching a peak concentration about 2 to 3 h after an oral dose. Peak and trough concentrations for the 1,200-mg dose were 907 and 194 ng/ml, respectively. Total body clearance was 10 to 18 liters/h. Oral bioavailability was 12 to 20%. The drug was moderately bound to plasma proteins with a free fraction of 29 +/- 2% (mean +/- standard deviation). About 10% of an administered intravenous dose of rifabutin is excreted into the urine unchanged. Renal clearance was 1.5 +/- 0.2 liters/h. The volume of distribution was large (8 to 9 liters/kg), suggesting extensive distribution into the tissues. The area under the curve for the last dose was smaller than that of the first dose, suggesting possible induction of drug-metabolizing enzymes.     

Pharmacokinetics of GLQ223 in rats, monkeys, and patients with AIDS or AIDS-related complex.

The pharmacokinetics of GLQ223 administered as a single short intravenous infusion to rats, monkeys, and patients with AIDS or AIDS-related complex (ARC) are presented. GLQ223 was given at a dose of 3,500 micrograms/kg of body weight to five Sprague-Dawley rats; a dose of 300 micrograms/kg was given to three cynomolgus monkeys; and doses of 1, 8, 16, 24, and 36 micrograms/kg were given to 10 patients with AIDS and 8 patients with ARC in an escalating dose design. Plasma clearance was 0.85 +/- 0.24 liter/h/kg in rats, 0.16 +/- 0.08 liter/h/kg in monkeys, and 0.13 +/- 0.07 liter/h/kg in patients with AIDS or ARC. The volume of distribution at steady state was 0.42 +/- 0.12, 0.21 +/- 0.20, and 0.18 +/- 0.50 liter/kg in rats, monkeys, and patients, respectively. The elimination half-life was 1.3 +/- 0.4, 3.7 +/- 1.5, and 3.2 +/- 1.0 h in rats, monkeys, and patients, respectively. The disposition of GLQ223 was not dose dependent within the dose range tested in patients with AIDS or ARC. Interspecies pharmacokinetic scaling resulted in a good linear correlation for plasma clearance and the volume of distribution at steady state plotted versus species body weight on a log-log scale, indicating the predictability of elimination and distribution of GLQ223 among species. Allometric equations derived may be useful for the prediction of doses and dosage regimens to be used in animal models.     

Disposition of hexobarbital in the rat. Estimation of "first-pass" elimination and influence of ether anesthesia

The disposition of hexobarbital was studied in rats after i.v. and i.a. administration. In addition to sleeping times, plasma concentration profiles were measured. No significant differences were found in sleeping times, volumes of distribution, elimination half-lives or systemic clearances between these different routes. The average elimination half-lives were 13.5 +/- 0.8 (n = 17) and 11.6 +/- 1.9 min (n = 21) (means +/- S.E.M.), respectively, whereas the systemic whole blood clearance values were 75.4 +/- 3.4 (n = 17) and 85.8 +/- 3.5 ml/min/kg (n = 21) (means +/- S.E.M.). The values of the latter parameter approach hepatic blood flow in the rat (i.e., 100 ml/min/kg) and therefore the oral availability of hexobarbital was established by comparing areas under plasma concentration time curves, after i.v. and oral administration to the same rat. Oral availability was found to be only 36%, which corresponds to an extraction ratio of 64%. The consequences of such a "first-pass" effect are discussed in view of the use of hexobarbital as a model substrate for measuring drug-metabolizing enzyme activity. Furthermore, it was found that anesthesia as induced by diethylether during the experiments resulted in a very significant inhibition of the rate of hepatic metabolism of hexobarbital; the elimination half-life increased by about 50% due to a similar decrease in the systemic clearance. The protein binding of hexobarbital in rat plasma amounted to 51.4 +/- 1.2% (mean +/- S.E.M., n = 15) and it was found not to be dependent on the plasma concentration of hexobarbital in the range encountered in vivo.