Glyn Taylor

The Pharmacokinetics of Pulmonary-Delivered Insulin: A Comparison of Intratracheal and Aerosol Administration to the Rabbit

The pulmonary deposition and pharmacokinetics of insulin, administered via an endotracheal tube as an aerosol and instillate, in formulations containing either 113mIn-DTPA or 99mTc-DTPA (for gamma scintigraphic imaging) have been studied in four male New Zealand White rabbits. Using a randomized crossover design, the pharmacokinetics of intravenous insulin were also characterized. Recovery of immunoreactive insulin after nebulization was greater than 90%, indicating that the aerosolisation procedure did not cause appreciable insulin degradation. Gamma scintigraphy demonstrated that the penetration index (peripheral:central deposition) for the aerosolized formulation (1.52) was much greater than that for the instillate (0.32). Gamma scintigraphy also allowed exact quantification of the dose deposited after aerosol administration and thus permitted accurate determination of bioavailabilities. The bioavailable fraction for aerosolized insulin was 10-fold greater than for instilled insulin (57.2 vs 5.6%). Mucociliary clearance was likely to be greater for the instillate since it showed a preferential central deposition; this may account for the lower bioavailability. Insulin pharmacokinetics from both pulmonary formulations were absorption rate limited, resulting in postpeak half-lives which were approximately 20-fold greater than the intravenous elimination half-life (3 min). The apparent absorption rate constants resulting from instillation and aerosolisation were statistically equivalent (0.015 and 0.011 min−1, respectively). Mucociliary clearance of insulin would result in an overestimation of the true absorption rate constant; hence if mucociliary transport were greater for the instillate, then the true airways to blood transfer rate constant will be higher for the aerosolized formulation.

The stability of liposomes to nebulisation

Abstract The stability of liposomes to aerosolization was determined by analyzing the aerosol produced from liposomal formulations using a mulistage liquid impirger. These investigations indicated a large loss of entrapped drug on passage of multilamellar vesicles and reverse-phase evaporation vesicles through an air-jet nebuliser, due to fragmentation of vesicles. Reducing the size of vesicles by extrusion of preparations through polycarbonate membrane filters decreased the extent of drug loss during nebulisation. Regional deposition of the aerosolized product within the multistage liquid impinger was governed by the size of the aerosol droplets rather than that of the liposomes.

The influence of liposomal encapsulation on sodium cromoglycate pharmacokinetics in man.

The pharmacokinetics of pulmonary-administered sodium cromoglycate (SCG) has been studied in five healthy volunteers. SCG, 20 mg, was inhaled as a solution and encapsulated in dipalmitoyl phosphatidylcholine/cholesterol (1:1) liposomes. Liposomal SCG produced detectable drug levels in plasma from four volunteers taken 24 and 25 hr after inhalation. Inhaled SCG solution, although producing peak plasma levels more than sevenfold greater than liposomal drug, was not detectable in 24-hr samples from any volunteer. The decline in plasma levels following inhalation of liposomal SCG (reflecting the absorption phase) was best described by a biexponential equation. The two absorption rate constants differed by more than an order of magnitude. The rapid absorption phase was probably due to free or surface-adsorbed SCG in the liposomal formulation, since the absorption rate constant for this phase did not differ significantly from the absorption rate constant for SCG in solution. The phase of slow drug absorption may then be attributed to absorption of drug released from vesicles. The data indicate that encapsulation of SCG prior to pulmonary administration prolonged drug retention within the lungs and altered its pharmacokinetics.

Drug entrapment and release from multilamellar and reverse-phase evaporation liposomes

Abstract The entrapment of sodium cromoglycate was determined in multilamellar liposomes prepared from natural and synthetic phospholipids. Drug entrapment was low, but was increased by inclusion of cholesterol or stearylamine into vesicle bilayers. Reverse-phase evaporation vesicles entrapped greater amounts of drug than multilamellar liposomes of the same composition. The rate of drug efflux from liposomes was determined in vitro and was dependent upon bilayer composition and the method of preparation.

The Influence of Regional Deposition on the Pharmacokinetics of Pulmonary-Delivered Human Growth Hormone in Rabbits

The pulmonary deposition and pharmacokinetics of human growth hormone (hGH), administered by aerosol and instillate, in formulations containing 99mTc-DTPA (for gamma scintigraphic imaging) have been studied in five male New Zealand White rabbits. Gamma scintigraphy indicated that the peripheral:central deposition tended to be greater for aerosol (1.54) than for instillate (0.8). Two gamma scintigraphic methods were used to quantify dose deposited by aerosol, which permitted bioavailabilities to be determined. The bioavailable fraction for aerosolized hGH (45%) was greater than for instilled hGH (16%). This was attributed to the differential effects of mucociliary clearance. Absorption rate limited pharmacokinetics prevailed for both hGH formulations with post-peak half-lives approximately 10-fold greater than the intravenous elimination half-life of 40 min. Apparent absorption rate constants resulting from instillation and aerosolization were equivalent (0.0012 min−1and 0.0020 min−1respectively), however lung-to-blood transfer rate constants for aerosol delivery (0.00071 min −l) were greater than for instillation (0.00018 min−1).

Studies of cyclodextrin inclusion complexes. III. The pulmonary absorption of β-, DM-β- and HP-β-cyclodextrins in rabbits

The fate of β-cyclodextrin (β-CYD) and some of its derivatives is reported following pulmonary administration in order to evaluate the feasibility of using β-CYDs for sustaining pulmonary drug action or for controlling systemic drug levels following pulmonary administration. Using a randomised cross-over design, the absorption and pharmacokinetics of β-, dimethyl(DM)-β-and 2-hydroxypropyl(HP)-β-CYDs have been investigated in five healthy New Zealand White male rabbits, after intravenous bolus dosing (i.v.) by means of a marginal ear vein and pulmonary administration via intratracheal instillation (i.t.) at the bifurcation of the trachea. No significant difference was found between the i.v. and i.t. terminal half-life (t12.z) for β- or DM-β-CYDs, indicating the absence of pulmonary absorption rate-limited kinetics. The clearance of each CYD (3.4–3.9 ml/min per kg) was similar to the glomerular filtration rate. The steady-state volume of distribution (184–214 ml/kg) is fairly small, approximating that of extracellular fluid volume, indicating extravasation of the CYDs. Although the bioavailable fraction (66–80%) is similar for all CYDs, the HP-β-CYD is absorbed more slowly than the others (mean absorption time approx. 113 min compared to 26 and 21 min for β- and DM-β-CYDs, respectively). The times required to reach the maximum plasma level for β-, DM-β- and HP-β-CYD were 30, 22 and 113 min, respectively. From these studies it is concluded that of the three CYDs tested, HP-β-CYD has the best potential as a drug carrier for sustaining pulmonary release.

The absorption and metabolism of xenobiotics in the lung

Abstract Factors influencing the absorption and metabolism of non-volatile xenobiotics have been considered. A number of physiological and pathological variables, including deposition site, distension, disease states, age, sex and species, influence the absorption of xenobiotics. Additionally, physicochemical properties of the xenobiotic including lipophilicity and diffusivity are important in determining its absorption. The lung has a range of enzyme systems and the potential to metabolize a broad variety of xenobiotics. Metabolism within the lung may result in first-pass elimination of drugs administered via the airways and may contribute to the clearance of systemically circulating compounds. Whilst many of the enzyme systems present in lung are similar to those in liver there are important differences in the isozymes of particular enzymes, including cytochrome P-450 and flavin-containing monooxygenase, present in each organ.

Mode of Breathing—Tidal or Slow and Deep—through the I-neb Adaptive Aerosol Delivery (AAD) System Affects Lung Deposition of 99mTc-DTPA

BACKGROUND The I-neb AAD System was designed to deliver aerosol with two different breathing pattern algorithms: the Tidal Breathing Mode (TBM) and the Target Inhalation Mode (TIM). For the purpose of the study, the TBM breathing pattern algorithm was set to guide the subjects to inhalation during tidal breathing with aerosol pulsed during 50-80% of the time spent on inhalation, whereas the TIM breathing pattern was set to guide the subject to a slow and deep inhalation of up to approximately 9 sec with aerosol pulsed for up to 7 sec, leaving 2 sec for particle deposition in the lungs. In TIM, the inspiratory flow was guided to approximately 20 L/min through a built-in resistance in the mouthpiece. METHODS We have, in a randomized, open-label, crossover study of 12 healthy subjects evaluated lung deposition following administration of a radiolabeled aerosol from the I-neb AAD System with the TBM and TIM breathing patterns. RESULTS The results showed that mean lung deposition was significantly higher when using the I-neb AAD System with the TIM breathing pattern (73.3%) than with the TBM breathing pattern (62.8%). The mean exhaled fractions were low (<1%) for both breathing patterns. The nebulization time was significantly shorter with the TIM breathing pattern (3.0 min) than with the TBM breathing pattern (4.7 min). CONCLUSIONS The results of the present study showed that lung deposition with the slow and deep inhalation achieved through the I-neb AAD System in TIM was superior to the lung deposition achieved during tidal breathing in TBM. With the combination of high lung deposition, almost no loss of aerosol during exhalation, and short nebulization time the I-neb AAD System with the TIM breathing pattern should be of special value to patients who require multiple daily dosing of aerosolized medication, are using drugs that should not be wasted into the room air, or would benefit from a more efficient delivery system.

Studies of cyclodextrin inclusion complexes. IV. The pulmonary absorption of salbutamol from a complex with 2-hydroxypropyl-β-cyclodextrin in rabbits

Abstract The present study details the fate of an HP-β-CYD-salbutamol complex following pulmonary administration in order to evaluate the possibility of obtaining sustained release of salbutamol using HP-β-CYD as a carrier. Using a randomised cross-over design, the absorption and pharmacokinetics of HP-β-CYD-salbutamol complex have been investigated in four healthy New Zealand White male rabbits, after intravenous bolus (i.v.) by means of the marginal ear vein and pulmonary administration via intratracheal instillation (i.t.) at the bifurcation of the trachea. Although the terminal half-life of salbutamol did not change significantly after complexation, the pulmonary absorption of salbutamol as a complex was prolonged, as shown by its maximum plasma concentration which was observed approx. 23 min after instillation compared to approx. 14 min for the uncomplexed salbutamol, and also by the increased absorption time. However, the availability of the complexed salbutamol was reduced to about 80% of that of the free drug compared to that seen after i.v. dosing. The plasma profile for HP-β-CYD was shown to be identical when administered as a complex with salbutamol and in its absence. Complexation did not sufficiently extend the salbutamol release profile to justify its use as a sustained release formulation. However, this approach to achieving prolonged pulmonary drug release profiles may be appropriate for drugs exhibiting stronger complexes with HP-β-CYD or prompt a search for CYD derivatives having a better complexing ability for salbutamol.

Partitioning of Oxamniquine into Brain Tissue Following Intravenous Administration to Female Wistar Rats

ABSTRACTBrain and plasma concentrations of oxamniquine were determined following intravenous dosing (15 mg kg1) in female Wistar rats. Maximum brain concentrations were achieved one hour after dosing and at all sampling times oxamniquine levels were higher in brain tissues compared to the corresponding plasma samples.