A review of recent experiments on step-to-step "hand-off" of the DNA intermediates in mammalian base excision repair pathways.

The current "working model" for mammalian base excision repair involves two sub-pathways termed single-nucleotide base excision repair and long patch base excision repair that are distinguished by their repair patch sizes and the enzymes/co-factors involved. These base excision repair sub-pathways are designed to sequester the various DNA intermediates, passing them along from one step to the next without allowing these toxic molecules to trigger cell cycle arrest, necrotic cell death, or apoptosis. Although a variety of DNA-protein and protein-protein interactions are known for the base excision repair intermediates and enzymes/co-factors, the molecular mechanisms accounting for step-to-step coordination are not well understood. In this review, we explore the question of whether there is an actual step-to-step "hand-off" of the DNA intermediates during base excision repair in vitro. The results show that when base excision repair enzymes are pre-bound to the initial single-nucleotide base excision repair intermediate, the DNA is channeled from apurinic/apyrimidinic endonuclease 1 to DNA polymerase beta and then to DNA ligase. In the long patch base excision repair sub-pathway, where the 5'-end of the incised strand is blocked, the intermediate after polymerase beta gap filling is not channeled from polymerase beta to the subsequent enzyme, flap endonuclease 1. Instead, flap endonuclease 1 must recognize and bind to the intermediate in competition with other molecules.

A novel A1 adenosine receptor antagonist, L-97-1 [3-[2-(4-aminophenyl)-ethyl]-8-benzyl-7-{2-ethyl-(2-hydroxy-ethyl)-amino]-ethyl}-1-propyl-3,7-dihydro-purine-2,6-dione], reduces allergic responses to house dust mite in an allergic rabbit model of asthma.

Adenosine, an important signaling molecule in asthma, produces bronchoconstriction in asthmatics. Adenosine produces bronchoconstriction in allergic rabbits, primates, and humans by activating A1 adenosine receptors (ARs). Effects of L-97-1 [3-[2-(4-aminophenyl)-ethyl]-8-benzyl-7-{2-ethyl-(2-hydroxyethyl)-amino]-ethyl}-1-propyl-3,7-dihydro-purine-2,6-dione] a water-soluble, small molecule A1 AR antagonist were investigated on early and late phase allergic responses (EAR and LAR) in a hyper-responsive rabbit model of asthma. Rabbits were made allergic by intraperitoneal injections of house dust mite [HDM; 312 allergen units (AU)] extract within 24 h of their birth. Booster HDM injections were given weekly for 1 month, biweekly for 4 months, and continued monthly thereafter. Hyperresponsiveness was monitored by measuring lung dynamic compliance (Cdyn), after histamine or adenosine aerosol challenge in allergic rabbits. Hyper-responsive rabbits were subjected to aerosol of HDM (2500 AU), 1 h after intragastric administration of L-97-1 (10 mg/kg) solution or an equivalent volume of saline. Cdyn was significantly higher after treatment with L-97-1 compared with untreated controls (p < 0.05 n = 5). Histamine PC30 was significantly higher (p < 0.05; n = 5) after L-97-1 at 24 h compared with histamine PC30 at 24 h after HDM. Adenosine PC30 was significantly higher at 15 min and 6 h after L-97-1 compared with control (p < 0.05; n = 5). L-97-1 showed strong affinity for human A1 ARs in radioligand binding studies and no inhibition toward human phosphodiesterase II, III, IV, and V enzymes. These data suggest that L-97-1 produces a significant reduction of histamine or adenosine-induced hyper-responsiveness and HDM-induced EAR and LAR in allergic rabbits by blocking A1 ARs and may be beneficial as an oral therapy for human asthma.

In vitro microtuberization in potato (Solanum tuberosum L.) cultivars.

Mechanism of microtuberization in three elite cultivars kufri badhsha (KB), kufri chandramukhi (KCM) and kufri jawahar (KJ) of potato was studied. Sprouts of all the three cultivars were used to obtain in vitro shoot cultures. MS medium supplemented with chlorocholine chloride was found to be most suitable for all the cultivars. Maximum tuberization was obtained under incubation conditions of continuous darkness at 20 degrees +/- 1 degrees C. The highest number of micro-tubers per plant basis was produced under continuous darkness and KCM recorded the highest yield of micro-tubers and was found significantly superior to KJ and KB.

Disposition and pharmacokinetics of temozolomide in rat.

1. Temozolomide, an imidazotetrazine derivative, is a cytotoxic alkylating agent of broad-spectrum antitumour activity. The absorption, metabolism, distribution and excretion of temozolomide have been investigated in male and female Sprague-Dawley and Long-Evans rats following single oral or intravenous dose administration of 200 mg m(-2) non-radiolabelled or (14)C-radiolabelled temozolomide. The distribution of (14)C-temozolomide was also evaluated by whole-body autoradiography in male Sprague-Dawley rats. Plasma concentrations of temozolomide and its active metabolite 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC) were determined by high-performance liquid chromatography (HPLC) with ultraviolet detection. Plasma, urine and faeces were profiled by HPLC with radiochemical detection. 2. Temozolomide was rapidly and extensively (>90%) absorbed and widely distributed in tissues. The distribution pattern of radioactivity was gender independent. Penetration into the brain following oral or intravenous administration was 35-39% based on the brain/plasma AUC ratio. 3. Following intravenous or oral administration, temozolomide was primarily eliminated renally (75-85% of the dose) as either unchanged drug, a carboxylic acid analogue, AIC (a degradation product) and a highly polar unidentified peak. Biliary excretion was minimal (1.4-1.6%). The pharmacokinetics (oral versus intravenous) were similar and gender independent. The absolute oral availability was 96-100%. Temozolomide was rapidly eliminated (t(1/2) = 1.2 h) and converted to MTIC. 4. Systemic exposure to MTIC was about 2% that of temozolomide. Overall, the disposition of temozolomide in rats was similar to that observed in humans.

A population pharmacokinetic model that describes multiple peaks due to enterohepatic recirculation of ezetimibe.

BACKGROUND: Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, is in clinical development for the treatment of hypercholesterolemia. It is rapidly absorbed and glucuronidated in the intestine. The parent compound and its conjugated metabolite undergo enterohepatic recirculation, resulting in multiple peaks in the plasma concentration-time profile. OBJECTIVE: The purpose of this study was to develop a population pharmacokinetic (PPK) model for ezetimibe that incorporates enterohepatic recirculation. METHODS: A population compartment model incorporating input from the gallbladder, consistent with food intake, was developed to account for enterohepatic recirculation. The amount recycled was allowed to vary within a subject and between subjects, accommodating variability in bile secretion. The data used consisted of 90 profiles from healthy subjects who received single or multiple doses of ezetimibe 10 or 20 mg. Modeling was carried out using a nonlinear mixed-effect function in the S-PLUS statistical program. RESULTS: The amount of ezetimibe recycled into the central compartment was estimated to be approximately 17% to 20% of the total amount absorbed, independent of the volume of distribution. The intersubject coefficient of variation was 46% to 80% in the absorption rate constant, 27% in the distribution phase, and approximately 50% in the volume of distribution. CONCLUSIONS: PPK models adapted for enterohepatic recirculation allowed a formal assessment of the magnitude and frequency of the enterohepatic recirculation process, and the associated intersubject and intrasubject variability in healthy subjects. The PPK approach also helped to assess the correlation between the observed maximum or minimum (24 hours postdose) concentration with the model-based area under the curve, confirming the appropriateness of the former measures as a surrogate of drug exposure for a possible correlation with pharmacodynamics.

Population pharmacokinetics of temozolomide in cancer patients.

PURPOSE: To evaluate covariate effects on the pharmacokinetics of temozolomide in cancer patients, and to explore the dose-pharmacokinetics-toxicity relationship of temozolomide. METHODS: Non-linear mixed-effects modeling approach was used to analyze the data from 445 patients enrolled in eleven Phase I and Phase II clinical trials. All patients in the phase I trials had advanced cancer. Patients in the phase II trials had anaplastic astrocytoma (AA), glioblastoma multiforme (GBM) or malignant melanoma (MM). A sparse sampling scheme was prospectively developed using Phase I data and was successfully implemented in Phase II trials. Population factors included age, gender, height (HT), weight (WT), body surface area (BSA), serum creatinine (Sr.Cr.), estimated creatinine clearance, serum chemistry data as indices of hepatic function and disease, smoking status, and selected concomitant medications. Descriptive statistics were used to summarize the toxicity and temozolomide dose and exposure relationship. RESULTS: The pharmacokinetics of temozolomide follows a one-compartment model with first order absorption and elimination. Temozolomide clearance (CL) increased with BSA for both genders. The population mean clearance for GBM or AA patients was 11.2 L/hr for male with BSA equal to 2.0 m2, and 8.8 L/hr for female with BSA equal to 1.7 m2. The mean clearance for MM patients was slightly higher. The inter-subject variability in clearance was 15%, and the residual variability was 26%. Other factors investigated in this analysis had little effect on clearance. The overall incidence of neutropenia and thrombocytopenia were 5-8%. Temozolomide dose and AUC did not predict nadir neutrophil and platelet counts due to large variability in counts. CONCLUSIONS: The current dose regimen is administered according to BSA which is the most important factor influencing temozolomide clearance. No further dose adjustment is required.

Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine.

AIMS: To evaluate whether ketoconazole or cimetidine alter the pharmacokinetics of loratadine, or its major metabolite, desloratadine (DCL), or alter the effects of loratadine or DCL on electrocardiographic repolarization in healthy adult volunteers. METHODS: Two randomized, evaluator-blind, multiple-dose, three-way crossover drug interaction studies were performed. In each study, subjects received three 10 day treatments in random sequence, separated by a 14 day washout period. The treatments were loratadine alone, cimetidine or ketoconazole alone, or loratadine plus cimetidine or ketoconazole. The primary study endpoint was the difference in mean QTc intervals from baseline to day 10. In addition, plasma concentrations of loratadine, DCL, and ketoconazole or cimetidine were obtained on day 10. RESULTS: Concomitant administration of loratadine and ketoconazole significantly increased the loratadine plasma concentrations (307%; 90% CI 205-428%) and DCL concentrations (73%; 62-85%) compared with administration of loratadine alone. Concomitant administration of loratadine and cimetidine significantly increased the loratadine plasma concentrations (103% increase; 70-142%) but not DCL concentrations (6% increase; 1-11%) compared with administration of loratadine alone. Cimetidine or ketoconazole plasma concentrations were unaffected by coadministration with loratadine. Despite increased concentrations of loratadine and DCL, there were no statistically significant differences for the primary electrocardiographic repolarization parameter (QTc) among any of the treatment groups. No other clinically relevant changes in the safety profile of loratadine were observed as assessed by electrocardiographic parameters (mean (90% CI) QTc changes: loratadine vs loratadine + ketoconazole = 3.6 ms (-2.2, 9.4); loratadine vs loratadine + cimetidine = 3.2 ms (-1.6, 7.9)), clinical laboratory tests, vital signs, and adverse events. CONCLUSIONS: Loratadine 10 mg daily was devoid of any effects on electrocardiographic parameters when coadministered for 10 days with therapeutic doses of ketoconazole or cimetidine in healthy volunteers. It is concluded that, although there was a significant pharmacokinetic drug interaction between ketoconazole or cimetidine and loratadine, this effect was not accompanied by a change in the QTc interval in healthy adult volunteers.

Pneumadin-evoked intracellular free Ca2+ responses in rat aortic smooth muscle cells: effect of dexamethasone.

The direct vascular effect of pneumadin (PN) was determined by studying the changes in intracellular free calcium ([Ca2+]i) levels in cultured rat aortic smooth muscle cells maintained between the second and fifth passages. PN evoked a rapid, concentration-dependent, biphasic increase in [Ca2+]i. The [Ca2+]i level rose from a basal value of 108 nM to a maximum increase in peak value of 170 nM. Although the level of maximal [Ca2+]i response evoked by PN was less than with other vasoactive agonists, it was more potent (EC50 0.5 nM) than even endothelin-1 (EC50 3.1 nM). At concentrations > 100 nM, [Ca2+]i elevations induced by PN above basal levels were no longer observed. Pretreatment with dexamethasone (100 nM for 24 hr) resulted in a significant increase (P < 0.01) in the peak [Ca2+]i response (310 nM) to PN. However, the biphasic pattern in the peak [Ca2+]i responses encountered with increasing concentrations of PN remained unaffected. The exaggerated [Ca2+]i response to PN was abolished by preincubation of cells with either the glucocorticoid antagonist mifepristone (RU 486) or the protein synthesis inhibitor cycloheximide. Inclusion of either an AT1 antagonist (losartan), a V1 selective vasopressin antagonist (d(Ch2)5 Tyr (Me) AVP), or an alpha-adrenoceptor antagonist (phentolamine) failed to affect the increases in [Ca2+]i induced by PN. PN-evoked increases in inositol 1,4,5-trisphosphate levels paralleled the [Ca2+]i changes. These data suggest that PN increases Ca2+ mobilization in rat aortic smooth muscle cells via activation of phospholipase C coupled receptors. This effect is up-regulated by dexamethasone.

Pharmacokinetics of loratadine and pseudoephedrine following single and multiple doses of once- versus twice-daily combination tablet formulations in healthy adult males.

The pharmacokinetic profiles of single and multiple doses of loratadine, descarboethoxyloratadine (DCL) (the major active metabolite of loratadine), and pseudoephedrine were determined in a randomized, open-label, two-way crossover study in 24 healthy men. Subjects received a single dose (day 1) and multiple doses (days 3 to 10) of a once-daily (QD) formulation of loratadine 10 mg in an immediate-release coating and pseudoephedrine sulfate 240 mg in an extended-release core (CLAR-ITIN-D 24 HOUR tablets), and a twice-daily (BID) formulation of loratadine 5 mg in an immediate-release coating and pseudoephedrine sulfate 120 mg, with 60 mg in an immediate-release coating and 60 mg in the barrier-protected core (CLARITIN-D 12 HOUR tablets) in study sessions, each separated by a 10-day washout period. Both regimens were safe and well tolerated. On day 1, plasma loratadine, DCL, and pseudoephedrine concentrations were higher following the QD formulation than following the BID formulation, as expected. On day 10, loratadine and DCL maximum plasma concentration (Cmax) values were, on average, 87% and 35% higher, respectively, for the QD formulation than for the BID formulation; however, the values of the area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) for loratadine and DCL were equivalent (90% confidence interval [CI]: 83% to 110% for loratadine; 90% to 107% for DCL). On day 10, pseudoephedrine Cmax and AUC0-24 values were equivalent (90% CI for Cmax: 94% to 109%; for AUC: 91% to 106%) for the two formulations, and lower pseudoephedrine concentrations were observed from 16 to 24 hours with the QD formulation. Both loratadine/pseudoephedrine formulations produced equivalent loratadine and DCL AUC0-24 values and equivalent pseudoephedrine Cmax and AUC0-24 values following multiple dosing. The lower pseudoephedrine concentrations in the evening with the QD formulation may minimize the potential for insomnia in patients when compared with the BID formulation.

Characterization of AUCs from sparsely sampled populations in toxicology studies.

PURPOSE: The objective of this work was to develop and validate blood sampling schemes for accurate AUC determination from a few samples (sparse sampling). This will enable AUC determination directly in toxicology studies, without the need to utilize a large number of animals. METHODS: Sparse sampling schemes were developed using plasma concentration-time (Cp-t) data in rats from toxicokinetic (TK) studies with the antiepileptic felbamate (F) and the antihistamine loratadine (L); Cp-t data at 13-16 time-points (N = 4 or 5 rats/time-point) were available for F, L and its active circulating metabolite descarboethoxyloratadine (DCL). AUCs were determined using the full profile and from 5 investigator designated time-points termed "critical" time-points. Using the bootstrap (re-sampling) technique, 1000 AUCs were computed by sampling (N = 2 rats/point, with replacement) from the 4 or 5 rats at each "critical" point. The data were subsequently modeled using PCNONLIN, and the parameters (ka, ke, and Vd) were perturbed by different degrees to simulate pharmacokinetic (PK) changes that may occur during a toxicology study due to enzyme induction/inhibition, etc. Finally Monte Carlo simulations were performed with random noise (10 to 40%) applied to Cp-t and/or PK parameters to examine its impact on AUCs from sparse sampling. RESULTS: The 5 time-points with 2 rats/point accurately and precisely estimated the AUC for F, L and DCL; the deviation from the full profile was approximately 10%, with a precision (%CV) of approximately 15%. Further, altered kinetics and random noise had minimal impact on AUCs from sparse sampling. CONCLUSIONS: Sparse sampling can accurately estimate AUCs and can be implemented in rodent toxicology studies to significantly reduce the number of animals for TK evaluations. The same principle is applicable to sparse sampling designs in other species used in safety assessments.

P2X purinoceptors in the feline pulmonary vascular bed: distribution and selective in vivo pharmacological probes.

The distribution and identification of selective pharmacological probes for P2X purinoceptors in the pulmonary vascular (PV) bed of the cat have been investigated with autoradiographic and pharmacological techniques. Autoradiographic localization of the selective P2X purinoceptor ligand alpha, beta-[3H]methylene ATP (alpha, beta-MeATP) binding sites in cat lung shows that P2X purinoceptors are present in all vessels in the bed; high densities were present in large (2-mm diam) and small (0.5-mm diam) pulmonary arteries, bronchial arterioles (0.1-mm diam), and large pulmonary veins, whereas low density is characteristic of parenchymal arterioles and alveolar walls. Most of the binding is displaced with the P2X-purinoceptor agonist beta, gamma-methylene ATP and the putative selective P2X-purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) in all vessels; however, the binding is further displaced with the, P2Y-purinoceptor agonist 2-methylthio ATP (2-MeS-ATP), which suggests the presence of P2Y as well as P2X purinoceptors. P2X purinoceptors mediate potent vasoconstrictor actions in the PV bed. alpha, beta-MeATP is a selective agonist for P2X purinoceptors and does not act via serotonergic, histaminergic, adrenergic, or leukotriene vasoconstrictor receptors to produce an increase in PV resistance. The vasoconstrictor responses of alpha, beta-MeATP are attenuated by PPADS. However, PPADS has no effect on the vasodilation induced by ATP, adenosine, or 2-MeS-ATP. The diadenosine nucleotide AP5A also produced dose-dependent vasoconstrictor responses of the PV bed, which were approximately three times less potent than those of alpha, beta-MeATP and significantly reduced by PPADS. These data support that vasoconstrictor P2X purinoceptors are present on pulmonary vessels. The functional significance of these vascular P2X purinoceptors in the PV bed is not known; however, alpha, beta-MeATP, AP5A, and PPADS may be used in vivo to define their physiological role in health and disease in the lung.

Toxicokinetics/toxicodynamic correlations: goals, methods, and limitations.

Toxicokinetic (TK) studies are the basis for demonstrating dose-related drug exposure in animals and for ensuring that drug exposure is substantially greater in animals than that expected in humans at therapeutic doses. The usefulness of TK studies can be further enhanced by correlating TK parameters with relevant toxicologic end points. The so-called TK/toxicodynamic (TD) correlations can be extremely useful in bridging data from studies both within and across species and in designing early Phase I clinical trials. These correlations assume that toxicologic responses are comparable among species at comparable plasma concentrations. This assumption may apply for certain drugs but not for others. Therefore, TK/TD correlations should be developed and utilized on a case-by-case basis. Such correlations have proven to be extremely useful with anticancer drugs in formulating dose escalation strategies in cancer patients to rapidly attain the maximum tolerated and/or effective dose. However, these correlations have not been utilized effectively in other therapeutic areas. The development of TK/TD correlations, their scope, and limitations are discussed in this paper.

Angiotensin II elevates cytosolic free calcium in human lung adenocarcinoma cells via activation of AT1 receptors.

Angiotensin II (Ang II), bradykinin (BK), and endothelin-1 (ET-1) evoked alterations in cytosolic free calcium, [Ca2+]i, levels were determined using fura-2 fluorescence methodology in a human lung adenocarcinoma cell line (A549), a non-neoplastic lung cell line and a small cell lung carcinoma cell (SCLC) line. Ang II and BK evoked a rapid, concentration-dependent transient increase in [Ca2+]i in A549 cells. The peak [Ca2+]i increases attained with Ang II (1 microM) and BK (1 microM) were 3- and 4-fold higher, respectively (P < 0.01) than the basal [Ca2+]i values. This effect of Ang II was completely abolished by inclusion of losartan (DuP 753), an AT1 subtype selective antagonist. Removal of extracellular Ca2+ from the incubation medium led to significant diminution of the peak [Ca2+]i response to Ang II but not to BK. In contrast to Ang II and BK, ET-1 failed to evoke an increase in [Ca2+]i levels in A549 cells. Neither Ang II nor ET-1 evoked any appreciable increase in [Ca2+]i levels of non-neoplastic lung cell and SCLC cell lines. These data confirm that the human non-small cell lung cancer cells (A549) selectively express AT1 subtype receptors for Ang II that are functionally coupled to Ca2+ mobilization from both extra and intracellular sources.

ETB receptors on aortic smooth muscle cells of spontaneously hypertensive rats.

The effect of the agonist sarafotoxin 6c (S6c), selective for endothelin (ET) receptor subtype B (ETB), on cytosolic free Ca2+ concentrations ([Ca2+]i) was determined by fura-2 methodology using aortic smooth muscle cells (ASMC) isolated from spontaneously hypertensive rats (SHR) and two normotensive strains, Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats. The basal [Ca2+]i was significantly higher in the ASMC of SHR (139 +/- 8 nM) than WKY (107 +/- 7 nM) and SD (102 +/- 4 nM) rats. S6c produced concentration-dependent elevations in [Ca2+]i in the ASMC of WKY and SHR, whereas it did not evoke significant increases in the [Ca2+]i levels in the ASMC of SD rats. The peak [Ca2+]i levels observed with maximal concentrations of S6c (500 nM) was higher (P < 0.01) in the SHR (346 +/- 36 nM) than the WKY group (148 +/- 19 nM). The natural nonselective agonist, ET-1, evoked maximal [Ca2+]i in the ASMC of SHR, WKY, and SD rats of 635 +/- 43, 304 +/- 19, and 289 +/- 24 nM, respectively. Depletion of extracellular Ca2+ concentration led to the reduction of the peak [Ca2+]i response to ET-1 by 60 and 40% in the WKY and SHR cells, respectively, whereas the response to S6c remained unaffected. The ETA-selective antagonist, BQ-123 (1 microM), did not affect the [Ca2+]i response to S6c, whereas it attenuated the response to ET-1 by 90 and 70% in the WKY and SHR cells, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Pneumadin: a new lung peptide which triggers antidiuresis.

Normal mammalian lungs, including human fetal lungs, contain significant amounts of a decapeptide which releases arginine-vasopressin from the neurophypophysis and therefore has antidiuretic activity. The rat peptide is: Tyr-Gly-Glu-Pro-Lys-Leu-Asp-Ala-Gly-Val-NH2. The peptide from human fetal lungs has Ala instead of Tyr. It may be a normal regulatory substance and its role in the pathogenesis of the syndrome of inappropriate antidiuresis associated with lung diseases merits investigation. In view of its source and action, the antidiuretic lung peptide may be called Pneumadin.

Disposition of cefixime in the pregnant and lactating rat. Transfer to the fetus and nursing pup.

The disposition of cefixime, a potent, third generation, orally active cephalosporin, was characterized in the pregnant and lactating rat. After a single iv dose of 17.8 mg/kg 14C-cefixime to day 18 pregnant rats, the half-life for elimination of radioactivity from both maternal serum and placentas was 6.9 hr. Elimination from fetal plasma and tissues was somewhat longer, 12.5 and 13.7 hr, respectively. However, comparison of areas under the curve indicated that exposure of the fetuses to cefixime was far less than that of placentas. Whole body autoradiography showed the greatest radioactivity in maternal liver, kidney, and intestines. In the lactating rat, steady state plasma concentrations of 14C-cefixime were achieved by continuous ip infusion of 2.54 mg/kg/day via Alza osmotic Mini-pumps from days 10 to 14 postpartum. Plasma concentrations of radioactivity in the dams were, on the average, 70 times greater than in their nursing pups throughout the study. After 102 hr of drug infusion, total radioactivity in the body of the pups, including the stomach and intestinal contents, was 1% of the 14C-cefixime estimated to be in the mother's body at steady state. Overall, these data indicate that exposure of the developing rat fetus and nursing pup to cefixime after maternal drug administration is quantitatively small.

Dose-dependent pharmacokinetics of a new oral cephalosporin, cefixime, in the dog.

Cefixime (CL 284,635; FK 027) is a new third-generation oral cephalosporin. To study dose-dependent pharmacokinetics of cefixime in dogs, two balanced four-way crossover studies were conducted. In the first study, oral doses of 50, 100, and 200 mg/kg and an intravenous dose of 50 mg/kg cefixime were administered. In the second study, oral doses of 6.25, 12.5, and 25 mg/kg and an intravenous dose of 12.5 mg/kg cefixime were administered to the same dogs. A period of 1 month separated the two studies. When the two intravenous doses were compared (i.e., 12.5 and 50 mg/kg), a twofold increase in clearance and volume of distribution was observed after the higher dose. The oral systemic bioavailability in the dose range 6.25-50 mg/kg was 55%. It decreased to 44% at 100 mg/kg and 27% at 200 mg/kg. The average peak serum concentrations ranged from 15.8 micrograms/ml at 6.25 mg/kg to 119 micrograms/ml at 200 mg/kg. Within this concentration range, the fraction of free drug in serum (unbound to proteins) increased from 7 to 25%. This concentration-dependent protein binding was primarily responsible for changes in total clearance, volume of distribution, and bioavailability of the drug in dogs.

Pharmacokinetics of mitoxantrone in man and laboratory animals.

Mitoxantrone (NOVANTRONE), an anthracenedione, is a novel anticancer agent with a wide spectrum of antitumor activity. Its anticancer activity is comparable to that of doxorubicin but with apparently significantly reduced cardiotoxicity. The recommended dosage regimen for the treatment of breast carcinoma is 12-14 mg/m2 given intravenously once every 21 days. Intravenously administered mitoxantrone disappears from the plasma of man and laboratory animals with multiexponential kinetics and with the terminal half-life ranging from 38 h to several days. It is rapidly cleared from the plasma by extensive sequestration into the tissues of the rat, dog, monkey, and man. However, redistribution back into the plasma and elimination from the body are slow processes. In both animals and man it is metabolized to the mono- and dicarboxylic acid derivatives, as well as glucuronide conjugates of these acids. Following intravenous administration, it is unchanged mitoxantrone that binds to most tissues. Rats, dogs, monkeys, and man, all eliminate mitoxantrone and its metabolites slowly by both renal and biliary excretion, with the biliary route predominating.