Transition of lasing modes in disordered active photonic crystals.

The transition from a photonic band-edge laser to a random laser in two-dimensional active photonic crystals is described. The lasing modes in the active photonic crystals shift from the edge of the photonic bandgap to the bulk of the gap when a certain amount of position and size disorder is introduced. The shift of lasing modes is determined with various gain profiles. The results show that the modulation of lasing modes is significant when the lasing transition wavelength overlaps the photonic bandgap.

Oral bioavailability and first-pass effects.

Existing experimental strategies for the in vivo evaluation of factors affecting oral bioavailability have been reviewed. Based on concepts that have evolved, an integrated set of strategies emerges that appears capable of providing estimates of the individual contributions attributable to absorption, losses in the gut lumen, and first-pass elimination in the gut wall and the liver. The only assumptions are linear pharmacokinetics and constant clearance between treatments. These methods are also suitable for the assessment of metabolite bioavailability after drug administration and the quantitative determination of sites of biotransformation and metabolite formation in vivo.

Elementary osmotic pump for indomethacin.

Based on the principles of an elementary osmotic pump, systems were designed to deliver indomethacin in solution at a constant rate, Z, to contain a total amount of drug, Mt, and to deliver 80% of their content at time t80. To allow selection of the optimal delivery rate into the body, three different prototypes were prepared with respective values for Z, Mt, and t80 of: 7 mg/hr, 85 mg, 11 hr; 9 mg/hr, 85 mg, 8 hr; and 12 mg/hr, 85 mg, 6 hr. These systems were found to deliver 70% of each system's contents at zero-order rates. Delivery rates were independent of pH, method of measurement, and stirring rate. In keeping with these results, the systems in the GI tract of dogs delivered at the same rate as in vitro, which qualifies the in vitro test as a bioanalogous method predictive of the in vivo performance of the dosage forms. Preliminary results in normal volunteers yielded similar urinary recoveries, while plasma profiles were different from each other and distinct from those following conventional capsules.

Kinetics of osmotically controlled indomethacin delivery systems after repeated dosing.

Two osmotically driven, controlled-release dosage forms of indomethacin were evaluated in a multiple-dose crossover study in 12 healthy subjects. Following equivalent daily doses, less frequent dosing of both controlled-release forms resulted in plasma concentration profiles that are more uniform than those following capsule regimens. After the first day, morning predose plasma levels wer significantly higher for the controlled-release treatments. Renal clearances were similar between days and among treatments. Total urinary recoveries were comparable for all regimens.

Stereoselectivity in the disposition and metabolism of the uricosuric-diuretic agent, indacrinone, in Rhesus monkeys.

The physiological disposition following intravenous dosing of the separate enantiomers of indacrinone-14C (I), and of their major metabolite, 4'-hydroxyindacrinone-14C (M), was studied in the rhesus monkey. Pharmacokinetic analysis indicated that the disposition of I and M was stereoselective. In the case of the enantiomers of I, the areas under the curves of plasma concentration vs. time were about sevenfold greater for the (S)(+)- as compared to the (R)(-)-enantiomer. Renal and plasma clearances of (R)(-)-I were five to seven times greater than those of (S)(+)-I. Total urinary recovery of unchanged drug and metabolite accounted for 70% of the administered dose of either enantiomer. The systemic availability of (R)(-)-M from (R)(-)-I was approximately 21% of the dose, whereas that of (S)(+)-M from (S)(+)-I was only 4%. More pronounced differences were noted in the kinetics of metabolite disposition. The AUC values were about 27 times greater for (S)(+)-M than (R)(-)-M, and the renal and plasma clearances were approximately 25-fold higher for (R)(-)-M as compared to (S)(+)-M. The volume of distribution of (S)(+)-M was only 12% of that observed with (R)(+)-M. There was no evidence of glucuronide or sulfate conjugates of any of the enantiomers. These findings are consistent with the pharmacological activity attributed to the different enantiomers.

A liner mode of reversible metabolism and its application to bioavailability assessment.

A theoretical basis has been established for the bioavailability assessment of drug and metabolite wherein the biotransformation of one to the other is reversible. The method is applicable to linear systems and requires knowledge of drug metabolite clearance rates as well as the rate of their interconversion. While not necessary, an unconventional definition of plasma clearance appears desirable and expeditious. Depending on the experimental situation, clearance values may change between treatments; these changes should be recognized and accommodated. Alterations in experimental design are discussed as means to minimize the need for assumptions and/or to provide data in suitable form as tests of internal consistency.

Further considerations on model-independent bioavailability estimation.

Assumptions attendant to model-independent bioavailability estimation were reexamined. Particular attention was given to the situation where an intravenous reference is not available and nonrenal clearance is assumed to be constant between treatments. Under these circumstances, the previously proposed approximation was compared with other bioavailability estimators. On the basis of error analysis, a procedure was devised to yield optimal relative bioavailability estimates.

Kinetic parameter estimation by numerical algorithms and multiple linear regression: application to pharmacokinetics.

Two numerical examples are presented to illustrate the application of the proposed method of parameter estimation in pharmacokinetics. Results for a system exemplifying first-order kinetics indicate that parameters estimated by the proposed procedure compare favorably with those estimated by a nonlinear regression method. In a simulated example characterized by Michaelis-Menten elimination kinetics, the accuracy of the estimated parameters was comparable to that expected, verifying the validity of the method. The importance of the numerical approximation algorithms was demonstrated also.

Effects of concomitant aspirin administration on the pharmacokinetics of indomethacin in man.

Ten healthy volunteers each received single and multiple 50-mg doses of indomethacin orally and a single 25-mg dose of [14C]indomethacin intravenously in the absence of and concomitantly with 1200 mg of aspirin as a single dose and in a chronic t.i.d. regimen. Systematic analysis of the data resulted in the isolation and quantification of aspirin's effects on the absorption, distribution, biotransformation, excretion, enterohepatic circulation, and accumulation of indomethacin. The effects of chronic aspirin were to suppress the renal clearance, to increase the biliary clearance, to decrease the efficiency of gastrointestinal absorption, and to enhance the enterohepatic circulation of indomethacin. On concomitant administration of 1200 mg of aspirin t.i.d., mean plasma levels of indomethacin were depressed by 20% after a single oral dose, by a smaller margin after multiple oral doses, and not at all after a single intravenous dose of indomethacin. The mean plasma concentration of orally administered indomethacin was decreased by 8% when given concurrently with a single 1200 mg dose of aspirin. Concomitant chronic therapeutic dosages of indomethacin had no effect on salicylate accumulation from repetitive doses of aspirin.

Effect of lidocaine on the absorption, disposition and tolerance of intramuscularly administered cefoxitin.

The use of lidocaine HCL solution at concentrations of 0.5 and 1.0% to reconstitute sodium cefoxitin relieves the pain associated with intramuscular injections of the antibiotic. Cefoxitin absorption by the intramuscular route is initially rapid and is virtually complete. Peak serum concentrations, corresponding to about one-half those of a comparable intravenous infusion, are achieved in 30 min. Continuing absorption tends to maintain higher serum concentrations for longer times. Renal clearance and serum half-life of cefoxitin do not appear to be affected by lidocaine at its effective anaesthetic concentrations.

The disposition of sulindac.

The disposition of sulindac, a new nonsteroid anti-inflammatory drug, has been studied in normal volunteers in five separate clinical studies. Based upon material balance considerations, a minimum of approximately 88% of an oral dose is absorbed. The major biotransformations involve irreversible oxidation of the sulfinyl group of sulindac to sulfone and reduction to the corresponding sulfide. The latter, which all available evidence indicates to be the pharmacologically active form of sulindac, is not excreted in urine, and has an apparent terminal half-life of 18.2 hr, well suited to twice daily dosage of its pro-drug. Following twice daily dosage of sulindac for 5 days, plasma levels of sulfide approach an apparent steady state with concentrations varying only within a twofold range over each dosage interval. The reversible biotransformation between sulindac and its active sulfide metabolite provides the basis for two therapeutic advantages relating to the gastrointestinal intolerance usually associated with anti-inflammatory drugs: (1) circumvention of initial exposure of gastric and small intestinal mucosa to the active form of the drug and (2) maintenance of systemic levels of active drug by means of enterohepatic recycling, principally of inactive pro-drug.

Bioavailability assessment under quasi- and nonsteady-state conditions III: Application.

The applicability of bioavailability assessment at quasi- and nonsteady state is illustrated with data from a study comparing two formulations of amitriptyline hydrochloride in humans. Relative bioavailability as a function of the observed mean plasma concentrations may be expressed in closed form, provided the affected intervals begin and end in the log-linear region. Alternatively, numerical, graphical and/or electronic computational techniques may be used to stimulate the appropriate [Cp(i)]sim, the proximity of which to [Cp(i)]obs is a function of relative bioavailability and omega. If a model can be found to fit the data adequately, it would be sufficient that only one sampled interval end in the log-linear phase.

Pharmacokinetics of methyldopa in man.

Single doses of methyldopa were administered orally and intravenously as aqueous solutions to 12 healthy volunteers in a crossover study. Serial plasma and urine samples were analyzed specifically for methyldopa and its O-sulfate conjugate. Kinetic analyses of the results indicated that methyldopa disposition could be adequately represented by a two-compartment open model. Renal excretion accounted for about two-thirds of the plasma clearance of methylodopa. Absorption profiles were constructed with the aid of the pharmacokinetic model and contrasted with estimates of absorption which were model-independent. The mean fraction reaching the systemic circulation as methyldopa was estimated to be 0.25 (range 0.08-0.62 for n = 11). Although most of the absorption occurred within the first 5 hours oral administration, a minor component, suggestive of limited enterohepatic circulation, persisted from 9 to 36 hours. O-sulfate conjugation was route-dependent and appeared to be derived predominantly, if not exclusively, as a first-pass effect of absorption and/or enterophepatic circulation.

Bioavailability assessment under quasi- and nonsteady-state conditions II: study designs.

The flexibility of bioavailability assessment at quasi-and nonsteady state is demonstrated by systematically removing experimental constraints from the study design. Mathematical expressions are derived to describe each design variation. From the resultant solutions, it is evident that the proposed method can accommodate nonuniformities in dose, dosage interval, dosage regimen, dosing cycle, sampling interval, plasma half-life, washout period, and protocol adherence. Nominal requirements for the method are linear kinetics and mean plasma concentrations estimated over time intervals beginning and ending in the log-linear region.