Architecture of the drug-drug interaction network.

PURPOSE: Drug interaction information has been extensively compiled into large databases. The objective of the present study was to provide a systematic overview of the available drug interaction information, using a network approach. METHODS: The drug-drug interaction information was retrieved from a comprehensive source reference that documents primary drug interaction information over an extended period of time. With careful examination of the information, we identified three continuously growing databases that consisted of 351, 636 and 966 drugs and 742, 1858 and 3351 pairs of interaction, respectively. We then constructed three drug-drug interaction networks in which the interacting drugs were treated as nodes and were connected with links that represent interactions. For each network, we determined the number of interactions that each drug in that network has, and prepared histograms to show the frequency distribution. RESULTS: The frequency distribution or the probability that a given drug has k interactions, P(k), followed a power-law distribution, where the power law exponent was close to -1·5 and was independent of the network size. The results suggested that while the majority of the drugs in the network had few interactions (small k), highly interacting drugs (large k) were rare but contributed most of the network interactions. CONCLUSIONS: The present study demonstrated that drug interaction information can be viewed and analysed as a connecting, growing network. As with many real-world networks, the drug interaction network was scale free, indicating that drug interaction information has been dominated by a relatively small number of highly interacting drugs.

Methyltestosterone pharmacokinetics and oral bioavailability in rainbow trout (Oncorhynchus mykiss).

14C-methyltestosterone pharmacokinetics after intraarterial (2 and 20 mg/kg) and oral (30 mg/kg) administration were investigated in rainbow trout at 15 degrees C. Plasma concentrations of methyltestosterone were determined by reverse phase high performance liquid chromatography (HPLC) in combination with reverse isotope dilution for up to 6 and 12 days after oral and intraarterial administration, respectively. Methyltestosterone pharmacokinetic parameter values after intraarterial administration were determined using a two compartment model (WinNonlin). For the 2 and 20 mg/kg doses, respectively, the parameter values were, area under the plasma concentration-time curve (11.2 and 82.3 micromol h/l), total body clearance (0.640 and 0.903 l/h per kg), distribution half-life (4.13 and 8.23 h), elimination half-life (54.9 and 58.6 h), volume of the central compartment (3.83 and 13.9 l/kg), volume of distribution at steady state (6.06 and 26.8 l/kg), and the mean residence time (9.57 and 22.7 h). After oral administration, the following parameter values were assessed using a model-independent method, peak concentration (3.03 micromol/l), time of concentration peak (8.80 h), mean absorption time (13.8 h), and area under curve (AUC)(0-->infinity) (90.2 micromol h/l). A two compartment model analysis of the average plasma concentration-time profile after oral administration showed that absorption followed first-order kinetics with a half-life of 4.7 h. The oral bioavailability of methyltestosterone from food was about 70%.

Allometric scaling of xenobiotic clearance: uncertainty versus universality.

Statistical analysis and Monte Carlo simulation were used to characterize uncertainty in the allometric exponent (b) of xenobiotic clearance (CL). CL values for 115 xenobiotics were from published studies in which at least 3 species were used for the purpose of interspecies comparison of pharmacokinetics. The b value for each xenobiotic was calculated along with its confidence interval (CI). For 24 xenobiotics (21%), there was no correlation between log CL and log body weight. For the other 91 cases, the mean +/- standard deviation of the b values was 0.74 +/- 0.16; range: 0.29 to 1.2. Most (81%) of these individual b values did not differ from either 0.67 or 0.75 at P = 0.05. When CL values for the subset of 91 substances were normalized to a common body weight coefficient (a), the b value for the 460 adjusted CL values was 0.74; the 99% CI was 0.71 to 0.76, which excluded 0.67. Monte Carlo simulation indicated that the wide range of observed b values could have resulted from random variability in CL values determined in a limited number of species, even though the underlying b value was 0.75. From the normalized CL values, four xenobiotic subgroups were examined: those that were (i) protein, and those that were (ii) eliminated mainly by renal excretion, (iii) by metabolism, or (iv) by renal excretion and metabolism combined. All subgroups except (ii) showed a b value not different from 0.75. The b value for the renal excretion subgroup (21 xenobiotics, 105 CL values) was 0.65, which differed from 0.75 but not from 0.67.

Disposition of 14C-flumequine in eel Anguilla anguilla, turbot Scophthalmus maximus and halibut Hippoglossus hippoglossus after oral and intravenous administration.

The absorption, distribution and elimination of 14C-labelled flumequine were studied using whole body autoradiography and liquid scintillation counting. Flumequine was administered to eel Anguilla anguilla, turbot Scophthalmus maximus and halibut Hippoglossus hippoglossus intravenously and orally as a single dose of 5 mg kg(-1), corresponding to 0.1 mCi kg(-1). The turbot and halibut studies were performed in salt water (salinity of 32%) at temperatures of 16 +/- 1 degrees C (turbot) and 9.5 +/- 0.5 degrees C (halibut). The eel study was conducted in fresh water at 23 +/- 1 degrees C. In the intravenously administered groups flumequine was rapidly distributed to all major tissues and organs. After oral administration flumequine also appeared to have rapid and extensive absorption and distribution in all 3 species. After the distribution phase, the level of flumequine was higher in most organs and tissues than in the blood, except in muscle and brain. The most noticeable difference between the species was the slow elimination of flumequine from eel compared to turbot and halibut. In orally administered eels, substantial amounts of flumequine remained in all major organs/tissues for 7 d. At 28 d significant levels of flumequine were present in liver, kidney and skin (with traces in muscle), and at the last sampling point (56 d) in eye, bone, bile and posterior intestine. In orally administered turbot significant levels of flumequine were observed over 96 h in bile, urine, bone, skin, intestine and eye, and traces were detected over 28 d in bone and eye in addition to a significant level in bile. In orally administered halibut, significant levels of flumequine were observed in bile, skin, intestine and eye over 96 h. Traces were present in skin and eye over 7 d. The maximal flumequine concentrations in blood were calculated to be 2.5 mg equivalents l(-1) (eel at 12 h), 0.8 mg l(-1) (turbot at 6 h) and 0.6 mg l(-1) (halibut at 6 h) after oral administration.

Phase I trial of exisulind (sulindac sulfone, FGN-1) as a chemopreventive agent in patients with familial adenomatous polyposis.

Exisulind (sulindac sulfone; FGN-1), a metabolite of sulindac without known effects on prostaglandin synthesis, can promote apoptosis and inhibit tumorigenesis in preclinical systems. We performed a Phase I trial of this compound in patients with familial adenomatous polyposis (FAP) to examine the tolerability and safety of this drug in the cancer chemoprevention setting. Six patients each were treated with exisulind at doses of 200, 300, and 400 mg p.o. twice a day. Reversible hepatic dysfunction was noted in four of six patients treated at the 400-mg p.o., twice-a-day dose level, but in only one to two of six patients treated at each of the lower dose levels. The serum half-life of exisulind was 6-9 h; little drug accumulation was noted over time. A nonsignificant trend toward increased apoptosis in polyps was noted at the maximum tolerated dose, but no decrease in polyp numbers or significant effects on cellular proliferation was noted. After treatment, polyps tended to display a "halo" appearance grossly and mucinous differentiation histologically. The maximum safe dose of exisulind is 300 mg p.o. twice a day in patients with subtotal colectomies. Reversible hepatic dysfunction limits further dose escalation. A decrease in polyp numbers could not be demonstrated, but the trend toward increased apoptosis at the MTD and the observation of mucinous change histologically suggest that further investigation of drugs of this class might be warranted.

Maturation and growth of renal function: dosing renally cleared drugs in children.

A model was developed that characterized the maturation and growth of the renal function parameters (RFPs) glomerular filtration rate (GF), active tubular secretion (AS), and renal plasma flow (QR). Published RFP values were obtained from 63 healthy children between the ages of 2 days and 12 years. Maturation over time was assumed to be exponential from an immature (RFP(im)) to a mature (RFP(ma)) level; for growth, RFP(im) and RFP(ma) were assumed to follow the allometric equation: RFP (age, W) = aW(b)e(-kmat*age)+ cWb(1- e(-kmat*age)), where W is body weight, k(mat) is the maturation rate constant, b is the body weight exponent, and a and c are RFP(im) and RFP(ma) at unit W. The model-based equation was fitted to the age-W, RFP values by a nonlinear least-squares method. For GF, the maturation half-life was 7.9 months (90% maturation, 26 months), the body weight exponent was 0.662, and the ratio c/a (which reflected the magnitude of the maturation influence) was 3.1. For AS and QR, the maturation half-lives were about 3.8 months and the ratio c/a was about 1.8. For renally eliminated drugs, the model can be used to estimate dosing regimens that are based on the adult dosing regimen and the age and weight of the child.

Crop grouping: a proposal for public aquaculture.

Production in US aquaculture is limited by the few FDA-approved drugs available for use. The problem is compounded by the high costs and long time frames associated with extending the approved label of an existing drug to treat additional fish species. An FDA approved crop grouping plan could significantly reduce the costs associated with extending or expanding the label of a currently approved drug to other species. Before FDA could sanction such a plan, they require scientific data with which to make an informed decision. Under a crop grouping plan, a surrogate fish species would represent a single group of fish for the purposes of gaining drug approvals. The concept, if practical, would conserve substantial public resources expended to gain drug approvals and yet give regulators assurance that the extended label use provides necessary regulatory safeguards to protect human food safety and the environment. A crop grouping plan should include development of a data base that is sufficiently sensitive to discriminate differences of one group from another and yet would be able to identify potential similarities between like-species for grouping. The proposed crop grouping action plan should include data sets for fish grouped by temperature preference, activity level, and phylogenetic classification. Initially, two representative species would be identified for testing as surrogates for candidate groups; rainbow trout representing a coldwater, active, and conservative phylogenetic group, and channel catfish representing a warmwater, relatively sedentary and more phylogenetically advanced group. Additional species representing more primitive (sturgeon) and more advanced (striped bass and walleye) groups would be added. A waterborne (benzocaine) and an orally administered drug (sarafloxacin) would initially be tested among the major species groups. The integrity of the group will be tested by comparing the variability of response between major species against variability within cohort species identified for inclusion within each specific group.

Pharmacokinetics, tissue distribution and metabolism of acriflavine and proflavine in the channel catfish (Ictalurus punctatus).

1. The disposition of proflavine (PRO) and acriflavine (ACR) were examined in channel catfish after intravascular (i.v.) dosing (1 mg/kg) or waterborne exposure (10 mg/l for 4 h). 2. After i.v. dosing, plasma concentration-time profiles of parent PRO and ACR were best described by two- and three-compartment pharmacokinetic models respectively. Terminal elimination half-lives of PRO and ACR in plasma were 8.7 and 11.4 h respectively. 3. In animals dosed with 14C-PRO or 14C-ACR, total drug equivalent concentrations were highest in the excretory organs and lowest in muscle, fat and plasma. In PRO-dosed animals, residues in the liver and trunk kidney were composed primarily of glucuronosyl and acetyl conjugates of PRO; residues in muscle were composed mostly (> 95%) of the parent drug. In ACR-dosed animals, the parent compound comprised > 90% of the total residues in all tissues examined. 4. PRO and ACR were poorly absorbed in catfish during waterborne exposure. At the end of a 4-h exposure, parent PRO and ACR concentrations in muscle were 0.064 and 0.020 microgram/g respectively. Levels in muscle declined below the limit of determination (0.005 microgram/g) within 1-2 weeks.

A physiologically based pharmacokinetic and pharmacodynamic model for paraoxon in rainbow trout.

Trout were exposed to an aqueous solution of 75 ng/ml paraoxon for 5 days at 12 degrees C. The relationships among paraoxon concentration in water and target organs, AChE inhibition, and carboxylesterase (CaE) detoxification of paraoxon were characterized quantitatively by development of a PBPK-PD model. The PKPD model structure consisted of brain, heart, liver, kidney, and remainder of the body, which were interconnected by blood circulation. The paraoxon tissue/blood partition coefficients were: plasma/water, 1.46; liver/plasma, 5.89; brain/plasma, 3.90; heart/plasma, 2.91; kidney/plasma, 0.45; and blood/plasma, 0.91. Turnover of AChE was characterized from a dose-response study, in which its zero-order synthesis rate and first-order degradation rate constant were determined in several tissues; for brain they were 7.67 pmol/min and 7.31 x 10(-5) hr(-1). The uptake and depuration clearances of paraoxon (Cl(u) = 0.651 and Cl(d) = 0.468 ml min(-1) g body wt(-1)) were determined using a compartmental model. During continuous water exposure to paraoxon, AChE activity in the tissues declined to new steady state values that were maintained by the synthesis of new AChE. CaE was shown by simulation to be an important pathway for detoxification of paraoxon.

Liquid chromatographic determination of acriflavine and proflavine residues in channel catfish muscle.

A liquid chromatographic (LC) method was developed for determination of acriflavine (ACR) and proflavine (PRO) residues in channel catfish muscle. Residues were extracted with acidified methanol solution, and extracts were cleaned up with C18 solid-phase extraction columns. Residue concentrations were determined on an LC cyano column, with spectrophotometric detection at 454 nm. Catfish muscle was individually fortified with ACR (purified from commercial product) and PRO at concentrations of 5, 10, 20, 40, and 80 ppb (5 replicates per level). Mean recoveries from fortified muscle at each level ranged from 86 to 95%, with relative standard deviations (RSDs) of 2.5 to 5.7%. The method was applied to incurred residues of ACR and PRO in muscle after waterborne exposure of channel catfish to commercial acriflavine (10 ppm total dye for 4 h). RSDs for incurred residues of ACR and PRO were in the same range as those for fortified muscle. Low residue concentrations (< 1% of exposure water concentration) suggested poor absorption of ACR and PRO in catfish.

Characterization of proflavine metabolites in rainbow trout.

Proflavine (3,6-diaminoacridine) has potential for use as an antiinfective in fish, and its metabolism by rainbow trout was therefore studied. Fourteen hours after intraarterial bolus administration of 10 mg/kg of proflavine, three metabolites were found in liver and bile, and one metabolite was found in plasma using reversed-phase HPLC with UV detection at 262 nm. Treatment with hydrochloric acid converted the three metabolites to proflavine, which suggested that the metabolites were proflavine conjugates. Treatment with beta-glucuronidase and saccharic acid 1,4-lactone, a specific beta-glucuronidase inhibitor, revealed that two metabolites were proflavine glucuronides. For determination of UV-VIS absorption and mass spectra, HPLC-purified metabolites were isolated from liver. Data from these experiments suggested that the proflavine metabolites were 3-N-glucuronosyl proflavine (PG), 3-N-glucuronosyl,6-N-acetyl proflavine (APG), and 3-N-acetylproflavine (AP). The identities of the metabolites were verified by chemical synthesis. When synthetic PG and AP were compared with the two metabolites isolated from trout, they had the same molecular weight as determined by matrix-assisted, laser desorption ionization, time-of-flight MS. In addition, they coeluted on HPLC under different mobile phase conditions. Finally, the in vitro incubation with liver subcellular preparations confirmed this characterization and provided the evidence that APG can be formed by glucuronidation of AP or acetylation of PG.

Quantification of benzocaine and its metabolites in channel catfish tissues and fluids by HPLC.

Methods for extraction and gradient HPLC quantification were developed for benzocaine (BZ) and three of its metabolites to be used in conjunction with a reverse isotope technique. The metabolites were p-aminobenzoic acid (PABA), acetyl-p-aminobenzoic acid (AcPABA) and acetylbenzocaine (AcBZ). The matrixes studied were white muscle, red muscle, skin, liver, trunk kidney, head kidney, plasma and the bile of channel catfish. Analytes were validated for each of the compounds at 25 and 100 nmol per sample in the various tissues and fluids. The intraday variability (R.S.D.) was less than 13% in all tissues and fluids except for BZ in the liver. Recoveries varied from matrix to matrix for each analyte. The highest recoveries were obtained from plasma which ranged from 82.8-99.8% depending on the concentration. The average recovery of the compounds from tissues was between 50 and 78%, except for liver where the recovery of PABA and BZ was below 30%. Detection was by UV absorbance at 286 nm and the linear range was 2.5-15 nmol 100 ml-1 for all analytes. The method was selective; no interference peaks coeluted with the analytes.

Gas chromatographic determination of parathion and paraoxon in fish plasma and tissues.

A sensitive capillary gas chromatographic (GC) method for the simultaneous determination of the organophosphate insecticide, parathion, and its active metabolite, paraoxon, in biological samples was developed. This method involved a simple liquid-liquid extraction of parathion and paraoxon from water, plasma, or tissues and capillary GC determination using electron-capture detection and splitless injection; malathion was used as the internal standard. A gradient oven temperature program was used; the injection port and detector temperatures were 200 and 300 degrees C, respectively. These techniques allowed quantitative determination of parathion and paraoxon at 9-210-ng/ml. concentrations;recoveries ranged from 79.4 to 110.3% for tissues and from 91.9 to 100.0% for plasma and water. The within-day and between-day coefficients of variation were less than 8.0%. The method was used to characterize the pharmacokinetics of parathion and paraoxon and the tissue distribution of paraoxon in rainbow trout.

Influence of maturation and growth on cefetamet pivoxil pharmacokinetics: rational dosing for infants.

The pharmacokinetics of intravenous (i.v.) cefetamet and the bioavailability of oral cefetamet pivoxil in infants aged 3.5 to 17.3 months who were hospitalized for urological surgery were characterized. The absorption of cefetamet pivoxil administered in a syrup formulation was 38 +/- 19% (n = 5) for infants, which was comparable to values observed for children and adults. The plasma half-life of i.v. cefetamet was 3.03 +/- 0.96 h (mean +/- standard deviation; n = 20) in the infants. This was not different from the value observed for normal adult subjects but was longer than that reported for children aged 3 to 12 years. Urinary recovery of cefetamet after i.v. administration to infants was 63.4 +/- 17.7% (n = 16), which was less than the 80% recovery found in older children and adults. The steady-state volume of distribution was 399 +/- 116 ml/kg of body weight. It was comparable in size and showed the same dependence on body weight as it did in children and adults. The mean systemic clearance per kilogram of body weight in the infants was lower than that in children and adults, apparently because of immaturity of clearance processes. A model that accounted for maturation and growth with increasing age was developed for the clearance. On the basis of this model, the clearance capacity increased from birth to 5 years by a factor of 4.5 because of maturation. Maturation progressed exponentially, with a half-life of 14 months. This model was used to develop dosing regimen guidelines for pediatric patients aged 3.5 months and older.

Toxicokinetics of parathion and paraoxon in rainbow trout after intravascular administration and water exposure.

Fish are less sensitive than mammals to organophosphate insecticide toxicity. The species differences have been mainly investigated by biochemical studies of AChE and organophosphate interaction. To examine whether species differences in the toxicokinetics of the organophosphate insecticides were also involved in their differential toxicity, rainbow trout were fitted with a dorsal aorta cannula and administered parathion and its active metabolite paraoxon intraarterially (ia) and via water exposure. Serial blood samples were removed and the plasma concentrations of parathion and paraoxon were determined by capillary GC with EC detection. Plasma protein binding was determined by equilibrium dialysis and ultrafiltration. After ia injection the plasma concentration-time profiles of parathion and paraoxon were multiexponential, with a terminal t1/2 of 56.1 and 0.528 hr. The steady-state volumes of distribution and total body clearances (CLb) for parathion and paraoxon were 1370 and 1080 ml kg-1 and 21.4 and 3020 ml hr-1 kg-1; the plasma unbound fractions were 1.23 and 52.5%. The large difference in CLb between parathion and paraoxon appeared to result primarily from differences in plasma protein binding. Parathion had greater persistence in trout than rat, suggesting that sensitivity difference were unrelated to toxicokinetic differences.

Body size and the toxicokinetics of trifluralin in rainbow trout.

Rainbow trout (Oncorhynchus mykiss) ranging from 0.2 to 3395 g were exposed to trifluralin (TF) in water at concentrations of 0.6-2.0 micrograms/liter. Trout of all body sizes rapidly accumulated TF from the water. The uptake clearance (P, ml hr-1g-1) of TF from the water decreased as body weight (BW, g) increased. This decrease followed the allometric equation P (ml/hr) = 182.BW0.66. Other kinetic parameters affected by body size were the steady-state volume of distribution which had a BW exponent value of 1.07 and the biological half-life which increased in larger fish. The relatively larger volume of distribution in larger fish reflected an increased capacity for TF in peripheral compartment-associated tissues. Metabolic elimination and the bioconcentration factor of TF did not change systematically with changes in body size. Variation in total body lipid content could not adequately explain the increase in peripheral storage capacity for TF; the decreased plasma protein binding that was observed in larger trout may also have been involved.

Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in children.

The pharmacokinetics of cefetamet were determined after intravenous (i.v.) administration of cefetamet and oral administration of cefetamet pivoxil syrup to patients between the ages of 3 and 12 years. The patients were hospitalized for reconstructive urological surgery; to prevent infection, prophylactic i.v. cefetamet was administered on the day of surgery and oral cefetamet pivoxil was administered 2 days later. After i.v. administration, the mean (+/- standard deviation) half-life of cefetamet was 1.97 +/- 0.60 h (n = 18), which was different from the 2.46 +/- 0.33 h reported for nine adults (22 to 68 years old) in a previous study. The average values for the mean residence times were 2.35 +/- 0.94 and 2.83 +/- 0.34 h and the average values for the fraction of the dose eliminated unchanged in the urine were 79.9% +/- 8.99% and 80% +/- 11% in children and adults, respectively. Plots of mean systemic clearance and steady-state volume of distribution versus body weight for the children and comparative adults were linear on log-log coordinates, and the slopes of the plots were 0.661 and 0.880, respectively. These slope values suggested that mean systemic clearance values per unit of body surface area were similar in children and adults and that maintenance doses for children should be the adult maintenance dose multiplied by the child's surface area divided by 1.73 m2. The mean (+/- standard deviation) oral bioavailabilities of cefetamet pivoxil were 49.3% +/- 15.7% in 3- to 7-year-old children who received a 500-mg dose and 37.9% +/- 10.0% in 8- to 12-year-old children who received a 1,000-mg dose. These values were not different from that observed in the adult group after two 500-mg tablets. Likewise, the peak concentration of cefetamet in plasma and its time of occurrence in children were in line with the values which have been observed for adults.

Chronic ethanol consumption causes increased glucuronidation of morphine in rabbits.

1. Male rabbits were given an i.p. injection of 15 mg/kg morphine and plasma concentrations of morphine and morphine-3-glucuronide (M3G) were simultaneously quantified by h.p.l.c. After 14 days of 10% ethanol in the rabbits' drinking water, a second injection of morphine was administered and plasma concentrations were determined again. 2. Morphine plasma clearance increased significantly by 42% after ethanol treatment. The area under the plasma concentration time curve (AUC) for morphine decreased by 23% while the AUC for the glucuronide increased by 22%. 3. The ratio of the AUCs (glucruonide/morphine) increased by 72%. These results demonstrate that chronic ethanol treatment of rabbits results in increased clearance of morphine after an i.p. dose. The increase in clearance is most likely due to induction of UDP-glucuronosyltransferase isozymes by ethanol.