Salbutamol disposition and dynamics in conscious rabbits: influence of the route of administration and of the dose.

This study assessed the influence of dose and route of administration on salbutamol kinetics and hypokaliemic effect. Salbutamol plasma kinetics were studied in a first group of 6 rabbits who received 60, 800, and 60 micrograms/kg by the intravenous (iv), oral (po), and intratracheal (it) routes, respectively, at 1-week intervals. A second group of 6 rabbits received 120, 2400, and 120 micrograms/kg of salbutamol by the same three routes. Multiple blood samples were withdrawn to assay salbutamol and potassium. Following iv salbutamol (60 micrograms/kg), total plasma clearance was 82 +/- 5 ml/min per kg, apparent volume of distribution was 5.0 +/- 0.5 l/kg, and terminal half-life was 41 +/- 2 min. Similar values were estimated when 120 micrograms/kg of salbutamol was administered iv or was given po or it. The bioavailability of po and it salbutamol was approximately 1 and 20%, respectively. For the first group, the maximal decrease in plasma potassium elicited by salbutamol was 0.80 +/- 0.19, 0.48 +/- 0.22, and 0.78 +/- 0.46 mmol/l, and for the second group, maximal decrement was 1.31 +/- 0.37, 0.70 +/- 0.24, and 0.84 +/- 0.17 mmol/l for the iv, po, and it routes, respectively. Compared to salbutamol peak plasma concentrations, maximal decrease in plasma potassium appeared between 60 and 108 min later for the iv route, 90 and 25 min later for po and it routes, and for this reason, the hypokaliemic effect was not associated to salbutamol plasma concentrations. The hypokaliemic effect was dependent upon the route, e.g., po > it > iv.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of a Single Intravenous and Oral Dose of Pafenolol—a Beta1Adrenoceptor Antagonist with Atypical Absorption and Disposition Properties—in Man

The pharmacokinetics of pafenolol were studied in eight young healthy individuals. The doses were 10 mg iv and 40 mg orally. Each dose was labeled with 100 µCi [³H]pafenolol. The plasma concentration–time curve of the oral dose exhibited dual maxima. The second peak was about four times higher than the first one. Maximum concentrations were attained after 0.9 ± 0.2 and 3.7 ± 0.6 hr. The mean bioavailability (F) of the oral dose was 27.5 ± 15.5%. The reduction in F was due mainly to incomplete gastrointestinal absorption. The drug was rapidly distributed to extravascular sites; t _1/2l was 6.6 ± 1.8 min. The volumes of distribution were V _c = 0.22 ± 0.08 liter/kg, V _ss = 0.94 ± 0.17 liter/kg, and V _z = 1.1 ± 0.16 liters/kg. The iv dose of pafenolol was excreted in unchanged form in the urine to 55.6 ± 5.1% of the given dose and in the feces to 23.8 ± 5.7% within 72 hr. The corresponding recoveries of the oral dose were 15.8 ± 5.9 and 67.0 ± 10.2%, respectively. About 10% of both doses was recovered as metabolites in the excreta. Approximately 6% of the oral dose was metabolized to nonabsorbable compounds in the intestine. The mean total plasma clearance was 294 ± 57 ml/min, of which renal clearance, metabolic clearance, and gastrointestinal and/or biliary clearance were responsible for 165 ± 31, 31 ± 15, and 95 ± 32 ml/min, respectively. The half-life of the terminal phase determined from plasma levels up to 24 hr after dosing was 3.1 ± 0.3 hr for the iv dose and 6.7 ± 0.7 hr for the oral dose.     

Haemodynamic responses to salbutamol and isometric exercise are altered in young adults with mild asthma

Objectives: Tolerance to the haemodynamic effects of regularly inhaled ₂ agonists has been reported in a research setting. It is unclear whether cardiovascular responses in adults with asthma are influenced by their use in routine clinical practice. This study aimed to characterise the effects of acute salbutamol administration on systemic haemodynamics in adults with mild asthma who were receiving intermittent ₂ agonist treatment. Methods: Ten patients with mild asthma and ten healthy age and sex-matched controls were recruited to a randomised placebo-controlled double-blind two-way crossover study. Each received salbutamol 200 g or placebo, then performed sustained isometric handgrip exercise as an adrenergic cardiovascular stimulus. Heart rate and blood pressure responses were observed during rest and exercise, and cardiac index and systemic vascular resistance index were measured using non-invasive impedance cardiography. Results: Isometric exercise caused a greater increase in heart rate (12±3 vs. 8±3 bpm, P<0.01) and diastolic blood pressure (19±3 vs. 12±3 mmHg, P<0.01) in patients with asthma compared with healthy controls. Salbutamol administration significantly increased heart rate, blood pressure and cardiac index in healthy controls, but these responses were attenuated in patients with asthma. Conclusion: These findings indicate that adults with asthma, who are receiving intermittent ₂ agonist treatment, have a greater cardiovascular responses to sympathetic stimulation, and haemodynamic tolerance to acute salbutamol administration.     

Absorption and Disposition of a New Antiarrhythmic Agent Bidisomide in Man

Absorption and disposition of bidisomide were studied in 12 healthy male subjects after a 20-min iv (1 mg/kg; N = 6) infusion and oral (2 mg/kg; N = 6) administration of the ¹⁴C-labeled drug. The oral absorption profile of unlabeled bidisomide was also studied after administration of a solution by a nasoenteric tube to different sites of the gastrointestinal tract (stomach, duodenum, jejunum, and ileum). The systemic availability was 61%. Absorption was slow initially and then rapid, achieving peak plasma concentrations between 2 and 4 hr. Less than complete systemic availability was attributed to incomplete absorption rather than first-pass metabolism. When the drug solution was delivered directly to the stomach, two distinct peak plasma levels were found. This was attributed to the more rapid absorption of bidisomide in the duodenum and ileum (and/or possibly colon). Following an iv dose, plasma levels of the drug declined with mean half-lives of 0.11, 2.0, and 12 hr for , , and phases, respectively, and a plasma clearance of 380 mL/min. The percentages of the dose recovered as bidisomide in urine and feces were 19 ± 1 and 29 ± 4 for the iv dose and 9.1 ± 0.9 and 48 ± 5 for the oral dose. Bidisomide did not exhibit substantial enantioselective pharmacokinetics in plasma regardless of the route of administration. The mean urinary excretion of the (–) enantiomer was, however, slightly higher than that of the (+) enantiomer, with (–)/(+) enantiomeric ratios of 1.2 and 1.3 after iv and oral administration, respectively. The enantiomeric ratio of bidisomide recovered in the feces was approximately 1.     

Pharmacokinetics and absolute bioavailability of carteolol,a new β-adrenergic receptor blocking agent

Summary The pharmacokinetics and absolute bioavailability of a new nonselective -adrenoreceptor blocking agent, carteolol, were investigated after administration of single intravenous and oral doses to eight normal volunteers. Plasma and urine drug concentrations were measured by an HPLC method. The pharmacokinetic parameters after intravenous dosing were obtained by a two-compartment analysis: elimination or -phase t_1/2 4.7±0.3 h; Vc, 0.74±0.101/kg; Vd, 4.05±0.48 l/kg; Cl, 10.13±0.94 ml/min/kg; Cl_R, 6.56±0.58 ml/min/kg; and Cl_NR, 3.57±0.40 ml/min/kg. The absolute bioavailability obtained from plasma data was 83.7±8.0%, which was consistent with that derived from analysis of urine of 82.7±4.2%. The amounts excreted unchanged in urine up to 48 h after the intravenous and oral doses were 65.0±1.5% and 53.8±3.2% of the administered doses, respectively. The t_1/2 for removal of the drug derived from plasma and urine findings after intravenous and oral dosing were similar, which indicates that the main route of elimination of carteolol is via the kidneys. As the Cl_R of carteolol exceeded the Cl of creatinine there may be renal tubular secretion of the drug.     

Plasma concentrations of salbutamol in the treatment of acute asthma in a pediatric emergency. Could age be a parameter of influence?

Objective

The objective was to determine if the plasma concentrations of salbutamol, obtained during inhalation treatment of infantile acute asthma, are influenced by age range and by the aerosol system used.

Method

A randomized clinical trial was conducted in 46 children (1–5 years of age) with a diagnosis of acute asthma crisis, established in an emergency room pediatric service. Twenty-five children received salbutamol using a pressurized metered-dose inhaler with spacer (50 µg/kg), and 21 children received salbutamol by nebulization (150 µg/kg),three times during a 1-h period. At the end of the treatment, one blood sample was drawn and the plasma was stored for later determination of salbutamol concentration (liquid chromatography). Salbutamol plasma concentrations were compared in two age groups (≤2 years and >2 years of age). The type of device used (pressurized metered-dose inhaler or nebulizer) and the need of hospitalization were also tested. The Mann-Whitney U test was used with the level of significance set at 5% (P?<?0.05).

Results

No differences were detected regarding either the aerosol delivery system used or the need for hospitalization in relation to the plasma concentrations of salbutamol. However, higher plasma levels were found in patients >2 years vs patients ≤2 years [median (IQR): 9.40 (6.32–18.22) vs. 4.65 (2.77–10.10) ng/mL], demonstrating a significance difference (P?=?0.05).

Conclusion

Salbutamol plasma concentrations were influenced by age group of the patients submitted to inhalation therapy, even with doses adjusted for body weight. After correcting for the differences in the biovailabilities of the delivery systems, the concentrations were independent of the aerosol delivery device used.     

The extrapulmonary effects of inhaled hexoprenaline and salbutamol in healthy individuals

Summary We have investigated the cardiovascular and metabolic effects of multiple inhaled doses of salbutamol and hexoprenaline in 12 healthy volunteers. They inhaled 200 g of salbutamol or hexoprenaline at 15 min intervals for 60 min from a metered dose inhaler (total dose 1000 g). We measured heart rate, blood pressure, total electromechanical systole (as a measure of inotropic response), QT_c interval on the ECG, and plasma potassium at baseline, 10 min after each inhalation, and 30 and 60 min after the last inhalation.There was no difference in the effects of the two drugs on blood pressure, total electromechanical systole, or QT_c interval. Salbutamol significantly increased heart rate compared with hexoprenaline. Hexoprenaline caused a significantly greater fall in plasma potassium compared with salbutamol.     

Absolute Bioavailability and Absorption Profile of Cyanamide in Man

A pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (EC1.2.1.3) used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in healthy male volunteers following intravenous and oral administration. Cyanamide plasma levels were determined by a sensitive HPLC assay, specific for cyanamide. After intravenous administration cyanamide displayed a disposition profile according to a two-compartmental open model. Elimination half-life and total plasma clearance values ranged from 42.2 to 61.3 min and from 0.0123 to 0.0190 L · kg ^–1 · min^–1, respectively. After oral administration of 0.3, 1.0, and 1.5 mg/kg ± SEM values of C_max, t_max (median) and AUC were 0.18 ± 0.03, 0.91 ± 0.11, and 1.65 ± 0.27 g · ml ^–1 ; 13.5, 13.5, and 12 min; and 8.59 ± 1.32, 45.39 ± 1.62, and 77.86 ± 17.49 g · ml ^–1 · min, respectively. Absorption was not complete and the oral bioavailability, 45.55 ± 9.22, 70.12 ± 4.73, and 80.78 ± 8.19% for the 0.3, 1.0, and 1.5 mg/kg doses, respectively, increased with the dose administered. The models that consider a first-order absorption process alone (whether with a fixed or variable bioavailability value as a function of dose) or with loss of drug due to presystemic metabolism (with zero-order or Michaelis–Menten kinetics) were simultaneously fitted to plasma level data obtained following 1 mg/kg iv and 0.3, 1.0, and 1.5 mg/kg oral administrations. The model that best fit the data was that with a first-order absorption process plus a loss by presystemic metabolism with Michaelis–Menten kinetics, suggesting the presence of a saturable first-pass effect.     

Interindividual variability in the rate of salbutamol sulphation in the human lung

The ₂-adrenergic agonist salbutamol is administered by inhalation to treat lung-obstructive disease. Salbutamol is metabolized by conjugation with sulphate, and the sulphation of salbutamol was investigated in human lung. Specimens of lung were obtained at lobectomy from 11 non-smokers, 39 smokers and 46 ex-smokers, the latter refraining from smoking at least 6 months before surgery. Neither sex nor ageing influenced the activity of sulphotransferase. The rate of salbutamol sulphation (pmol·min^-1·mg^-1) was greater in non-smokers (27.7) than in smokers (21.3), whereas it was similar in smoker and ex-smokers (22.8). The rate of salbutamol sulphation ranged up to six fold and its distribution did not deviate from normality. As the rate of formation of the inactive salbutamol sulphate varied in the lung, the availability of salbutamol and, in turn, the evoked pharmacological effect should vary in parallel. The activities of salbutamol and dopamine sulphotransferase correlated, suggesting that catechol sulphotransferase takes part in the sulphation of salbutamol. The sulphation of salbutamol is stereoselective in the human lung, the k _M estimate for (+)-salbutamol (1198 M) being greater than those for either (-)-salbutamol (190 M) and racemic salbutamol (142 M). These results are consistent with the view that (-)-salbutamol is a better substrate than (+)-salbutamol for sulphotransferase.     

Correlation between the effects of salbutamol on contractions and cyclic AMP content of isolated fast — and slow — contracting muscles of the guinea pig

Summary The effects of isoprenaline and salbutamol on incomplete tetanic contractions of the isolated soleus (slow contracting) and extensor digitorum longus (EDL-fast-contracting) muscles of the guinea pig were studied and an attempt made to correlate these effects on contractility with changes in cyclic AMP concentrations. Salbutamol was 10–12 times less potent than (±)isoprenaline in decreasing the force of subtetanic contractions in the soleus and between 5–6 times less potent in increasing the force of subtetanic contractions in the EDL.This observation plus the lack of activity of both the selective ₁-adrenoceptor antagonist (atenolol) and the selective ₁ agonist (H 133/22) in the EDL implies involvement of ₂-adrenoceptors in these responses of the muscles to isoprenaline and salbutamol. The soleus muscle was about 6–12 times more sensitive to effects of -adrenoceptor agonists than the EDL. In concentrations which produced effects on muscle contractility, salbutamol significantly elevated cyclic AMP concentrations in both types of muscle. These effects were antagonised by propranolol. It seems clear that the contrasting effects of sympathomimetic amines on slow — and fast contracting muscle are mediated through a common mechanism — elevation of cyclic AMP. Possible explanations of this apparent paradox are discussed.     

Effect of salbutamol on digoxin pharmacokinetics

Summary A single dose of the ₂-adrenoceptor agonist salbutamol has previously been shown to decrease serum digoxin concentration in healthy volunteers. A possible explanation of the phenomenon is a ₂-adrenoceptor-mediated increase in the specific binding of digoxin to skeletal muscle. The present study was undertaken to further elucidate the effect of salbutamol on the pharmacokinetics of digoxin in man.Nine volunteers were studied on two occasions during salbutamol or placebo treatment. On test days salbutamol, 4 g·kg^–1·h^–1 or saline was infused for 10 h, preceded and followed by four and three days, respectively, of oral administration. A single i. v. injection of digoxin 15 g·kg^–1, was given 20 min after starting the infusion. At the end of the infusion a muscle biopsy was taken from the vastus lateralis. Blood samples for the analysis of serum digoxin and potassium were repeatedly taken over 72 h. Urine was collected over a period of 24 h for determination of the renal excretion of digoxin and potassium. The serum digoxin concentration, expressed as the AUC 0–6 h was 15% lower during salbutamol infusion than during saline infusion. Salbutamol caused significantly faster elimination of digoxin from the central volume of distribution to deeper compartments. Salbutamol had no effect on the renal clearance of digoxin. The skeletal muscle digoxin concentration tended to be higher (48%) during salbutamol compared to placebo treatment. The serum potassium concentration was significantly lower after salbutamol compared to placebo, as was the rate of renal excretion of potassium. The results support the hypothesis that the salbutamol-induced decrease in serum digoxin is caused by increased distribution of digoxin to skeletal muscle (and possibly other tissues), and that this may be secondary to a ₂-adrenoceptor-mediated increase in Na-K-ATPase activity.     

Investigation of the Distribution of EAB 515 to Cortical ECF and CSF in Freely Moving Rats Utilizing Microdialysis

A freely moving rat model was developed to study the CNS distribution of EAB 515 (S--amino-5-phosphonomethyl[l,1-biphenyl]-3-propanoic acid). Microdialysis (MD) in the frontal cortex (FrC) and in the lateral ventricle (LV) of the rat brain was performed to measure the levels of EAB 515 in the cortical extracellular fluid (ECF) as well as in the cerebrospinal fluid (CSF). The femoral artery and femoral vein were cannulated for serial blood sampling and intravenous (iv) drug administration, respectively. EAB 515 was also administered via the intracerebroventricular (icv) route in a cross-over experiment. The in vivo recovery of EAB 515 across the MD probes was determined by simultaneous retrodialysis (RD) performed using a hydroxylated analog of EAB 515, as the RD calibrator (RDC). An extremely sensitive and selective on-line HPLC system with native fluorescence detection was developed for the simultaneous analysis of EAB 515 and RDC in microdialysate samples from rat CSF and cortical ECF. Unbound concentrations of EAB 515 in the rat plasma were determined by direct injection of plasma ultrafiltrate onto the HPLC column. The validity of the use of RDC as the RD calibrator was demonstrated by comparing the results of zero-net flux (ZNF) analysis simultaneously in some experiments. After constant rate iv infusion in rats (n = 12) for 900 min, the average (S.D.) ratio of the levels of EAB 515 in the CSF to those in plasma C_csf,iv/C_p) was determined to be 17.7 (7.8)% and that in the cortex relative to plasma C_cortex,iv/C_p) was 8.3 (4.8)%. In these animals the total body clearance (Cl) of EAB 515 was estimated to be 8.5 ± 1.6 ml/min/kg. Upon icv administration in the lateral ventricle of rats (n = 6), a 136 ± 42-fold distribution advantage in the cortical ECF was determined. These results indicate a significant contribution from the transport across the CSF-Brain interface to the total uptake of EAB 515 by cortical tissue.     

Pharmacokinetics and pharmacodynamics of midazolam in the enflurane-anesthetized dog

Midazolam (Mid) is widely used as an anesthetic adjunct. To test its anesthetic effect vs. concentration relationships, it is desirable to establish stable and predictable Mid concentrations in plasma (and brain). Therefore, the pharmacokinetics of Mid in the enflurane-anesthetized dog were determined, and the ability of Mid to reduce the enflurane concentration required for anesthesia was measured and correlated with the Mid concentration in plasma [MID]. Mongrel dogs (n=9) were anesthetized with enflurane and the enflurane EC₅₀ (MAC—the end-tidal concentration at which one-half the dogs respond to the noxious stimulation of clamping of the tail, and one-half do not) was determined. Group 1 (n=5) received Mid 2.5mgJkg iv over 60 sec. Plasma for determination of [MID] was collected and the enflurane EC₅₀ was determined repeatedly over the 7–8-hr period following injection. Based on the pharmacokinetic parameters determined for Group 1, dogs in Group 2 (n=4) received Mid as a continuous infusion of 21 kg^–1 min^–1 for 5hr accompanied by an initial loading dose (3 mg/kg infused over 20 min) designed to produce a stable [MID] of 1000 ng/ml in plasma. Enflurane MAC and [MID] were determined regularly during the infusion and for 6hr after discontinuation of the infusion. There were no important differences in the pharmacokinetic parameters determined for Group 1 vs. Group 2: t_1/2,z=98±5 vs. 95±10min (mean ±SEM); V=3.94±0.27 vs. 2.98±25 L/kg; Cl=28.5±3.1 vs. 22.3±1.1 ml kg^–1 min^–1,respectively. When administered as a continuous intravenous infusion (Group 2), [MID] remained stable at 949 ± 53 ng/ml for more than 5hr. The enflurane EC₅₀ was reduced by 55% and the reduction remained stable during the 5 hours of Mid infusion. After a single iv bolus dose or after discontinuation of the continuous infusion, the degree of enflurane EC₅₀ reduction diminished toward the control (i.e., enflurane alone) value as [MID] declined. Midazolam's pharmacokinetics and plasma concentration vs. effect relationships have been determined to be consistent under two different experimental conditions.     

Influence of isoprenaline and salbutamol on the threshold of electrically inuced ventricular fibrillation in anaesthetized guinea pigs

Summary Fibrillation threshold and heart rate were measured after increasing doses of (–)-isoprenaline and (±)-salbutamol. The initial values of 212±10 A (x±SEM) and 211±10 A were decreased to 74±10 A by low doses of (–)-isoprenaline (10^–11 to 10^–10 moles/kg i.v.), and to 89±11 A by (±)-salbutamol (10^–9 to 10^–8 moles/kg i.v.). Higher doses, paradoxically, increased fibrillation threshold to initial values, (–)-isoprenaline: 2×10^–9 moles/kg; (±)-salbutamol: 2×10^–6 moles/kg. A linear increase in heart rate per 10-fold increase of either drug was observed, (–)-isoprenaline: 25 beats·min^–1; (±)-salbutamol: 14 beats·min^–1. The apparent ₂-selective property of salbutamol is documented by its low potency in changing fibrillation threshold and heart rate.     

A pharmacokinetic study of neostigmine in man using gas chromatography-mass spectrometry

Summary To permit rational evaluation of the empirical pharmacotherapy of myasthenia with cholinesterase inhibitors, a sensitive and selective method for the determination of neostigmine has been developed. Analysis is based on ion-pair extraction of neostigmine into methylene chloride and determination by gas chromatography-mass spectrometry (chemical ionization). As neostigmine was found to be metabolized in plasma in vitro, deuterated (d₆) neostigmine was immediately added to the plasma sample as the internal standard. The limit of quantitation of the method was about 1 ng/ml ( 3nmol/l). The kinetics following i. v. administration were studied in four patients, who received neostigmine 2.5–3.0 mg iv to antagonize pancurone administered during anaesthesia. Elimination was rapid with a half-life t_1/2 (-slope) of 0.89±0.05 h (mean ± SE). The volume of distribution was 1.08±0.11 l/kg and plasma clearance was 0.84±0.04 l/kg/h. In three fasting myasthenic patients plasma concentrations of neostigmine were followed for 5 h after a single oral dose of 30 mg. Considerable interindividual differences in absorption were expressed in the peak concentrations, which occurred 1–2 h following drug ingestion. The bioavailability of neostigmine was estimated to be 1–2% of the ingested dose. Neostigmine concentration in plasma was found to differ considerably (up to forty-fold) between myasthenic patients on their ordinary dose-schedules of cholinesterase inhibitors.     

Toxicokinetics ofN-nitrosodimethylamine in the Syrian golden hamster

The single-dose toxicokinetics ofN-nitrosodimethylamine (NDMA) has been characterized in 8-week-old male Syrian golden hamsters by analysis using high performance liquid chromatography of serial blood samples. An i.v. bolus dose of 4.2 mol/kg [¹⁴C]NDMA revealed biphasic first-order elimination with a terminal half-life of 8.7±1.0 min (mean±SE) for unchanged NDMA and 31.5±5.5 min for total radioactivity, and evidence for conversion to polar metabolites was seen in the chromatographic assays. The systemic blood clearance and apparent steady-state volume of distribution for unchanged NDMA were 51.2±3.0 ml/min/kg and 582±60 ml/kg, respectively. No unchanged NDMA was detected in the urine following an i.v. bolus dose of 15 mol/kg [¹⁴C]NDMA, but 31% of the total radioactivity was eliminated by that route. A dose of 38 mol/kg given by gavage indicated a systemic bioavailability of 11±4% for unchanged NDMA. Reversible binding of NDMA to hamster plasma proteins was found to be negligible. Estimation of the intrinsic hepatic clearance (Cl_I) in the hamster produced a value of 648 ml/min/kg, which is greater than that previously obtained for the rat, and indicates that the metabolic capacity of the hamster liver is greater than that of the rat. These results suggest that this difference in Cl_I may play a role in the previously reported (Lijinsky et al. 1987) switch in organotropism from almost exclusivity for liver tumors in hamsters dosed by gavage to additional high incidences of lung and kidney tumors in the rat.     

KATP channel openers reverse immune complex-induced airways hyperreactivity independently of smooth muscle relaxation

Many openers of ATP-dependent potassium channels (K_ATP channel openers) cause bronchorelaxation, whereas only a few of them have been claimed to reverse airways hyperreactivity. We investigated whether the antihyperreactive effect is a general feature of K_ATP channel openers and whether this property is linked to their ability to relax airways smooth muscle. For this purpose, the potency of the four K_ATP channel openers, bimakalim, rilmakalim, levcromakalim and SDZ PCO 400 ((–)-(3S,4R)3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3-oxo-cyclopent-lenyloxy)-2H-1-benzopyran-6-carbonitrile), to inhibit bombesin-or histamine-induced bronchoconstriction and to reverse immune complex-induced airways hyperreactivity to histamine in guinea pigs, was compared to salbutamol, following intratracheal administration to minimize pharmacokinetic differences.Total lung resistance (R_L) was determined in anaesthetized, ventilated guinea pigs. Bronchoconstriction, measured as increase in R_L, was elicited in normoreactive animals by i.v. infusion of bombesin (100 ng/kg/min) or by i.v. injection of histamine (1.8–10 µg/kg). Airways hyperreactivity was induced by acute i.v. administration of preformed immune complexes. I.v. bolus injections of histamine were used to define the sensitivity of the airways prior to and after the exposure to immune complex.Levcromakalim (ED₅₀ = 150 g/kg), bimakalim (ED₅₀ = 4 g/kg), rilmakalim (ED₅₀ = 40 g/kg) and SDZ PCO 400 (ED₅₀ = 280 g/kg) reversed bombesin-induced bronchoconstriction with lower potency than salbutamol (ED₅₀ = 1 g/kg). The four K_ATP channel openers and salbutamol also reversed immune complex-induced airways hyperreactivity to histamine with ED₅₀ values which were markedly lower than those for reversal of bombesin-induced bronchoconstriction; the rank order of potency was rilmakalim (ED₅₀ = 0.2 g/kg) > bimakalim (ED₅₀ = 0.5 g/kg) > SDZ PCO 400 (ED₅₀ = 3.2 g/kg) > levcromakalim (ED₅₀ = 22 g/kg). Salbutamol (ED₅₀ = 0.008 g/kg) was the most potent compound in this test. Bimakalim, levcromakalim and SDZ PCO 400 did not inhibit histamine-induced bronchoconstriction in normoreactive guinea pigs at doses which completely reversed immune complex-induced airways hyperreactivity to histamine. For rilmakalim and salbutamol, 60–130 times higher doses were needed for protection against histamine-induced bronchoconstriction in normoreactive guinea pigs than for reversal of airways hyperreactivity. There was a poor correlation between the ED₅₀ values for inhibition of histamine- or bombesin-induced bronchoconstriction in normoreactive guinea pigs and the reversal of immune cimplex-induced airways hyperreactivity. It is thus concluded that the ability of K_ATP channel openers to reverse immune complex-induced airways hyperreactivity is independent of their ability to reverse or prevent bronchoconstriction and thus from their ability relax airway smooth muscle.     

Effects of Hyperlipidemia on the Pharmacokinetics of Nifedipine in the Rat

Purpose. The effect of hyperlipidemia on nifedipine pharmacokinetics was studied. The mechanisms by which hyperlipidemia affects pharmacokinetics of drugs are mainly undetermined. Hyperlipidemia may decrease the fraction of unbound drug in plasma and/or decrease intrinsic ability of the cytochrome P-450 systems due to excess membrane cholesterol. Hyperlipidemia is a primary risk factor for coronary artery disease leading to hypertension and ischemic heart disease, for which nifedipine, a calcium channel blocker, is used. Methods. Poloxamer 407 (P407)-induced hyperlipidemic rat model was used to study the effects of hyperlipidemia on the pharmacokinetics of nifedipine (6 mg kg^–1 given iv, ip and po). Total plasma cholesterol levels increased from 0.82–2.02 to 5.27–11.05 mmol L^–1 48 h post P407 administration (Ig kg^–1, ip). Protein binding studies were conducted by an ultrafiltration method. Results. Hyperlipidemia significantly decreased CL_TB by 38% and CL_TB/F by 45 and 42% following po and ip doses, respectively, thereby increasing AUC_0–, C_max and half-life. Absolute bioavailability and Vd_ss remained unchanged. AUC_0– was affected to the same extent in each route of administration, therefore, the effect was mainly systemic rather than presystemic. Hyperlipidemia significantly lowered the fraction unbound in plasma by approximately 31%. Conclusions. The altered pharmacokinetics of nifedipine by P407-induced HYPERLIPIDEMIA may be, at least in part, due to the decrease in fraction unbound in plasma. A decrease in intrinsic clearance, however, cannot be ruled out.     

Pulmonary Delivery of Powders and Solutions Containing Recombinant Human Granulocyte Colony-Stimulating Factor (rhG-CSF) to the Rabbit

Two powder formulations (MMAD <4 µm) containing rhG-CSF were insufflated (IF) via an endotracheal tube at doses of 5, 75 or 500 µg/kg to New Zealand white rabbits. Doses of 5 and 500 µg/kg of solutions were administered by intratracheal instillation (IT), subcutaneous (SC) injection in the thigh and intravenous injection (IV) via the marginal ear vein. Blood samples were removed at regular intervals from an indwelling jugular catheter. Blood was analyzed directly for total white blood cell counts (WBC). Plasma was assayed for rhG-CSF by a specific ELISA. The distribution of radioactive dose in lung tissue was found after administering Tc99m HSA in solution or when incorporated into powders. The pharmacokinetics and pharmacodynamics were determined for all routes of administration. High dose IV concentration vs. time profiles declined biexponentially (t_1/2 = 0.6 ± 0.2 hrs, t_1/2 = 4.6 ± 0.2 hrs, n = 8). Clearance was dose dependent (11.6 ± 2.6 [500 µg/kg, n = 8] vs. 21.8 ± 3.3 ml/hr/kg [5 µg/kg, n = 5]). A normal systemic response was obtained after IF, indicating that rhG-CSF retains activity in the solid state. Dissolution and absorption of rhG-CSF from the powders were not rate limiting. The plasma concentration vs. time profiles peaked at similar times to those after IT (T_max 1 -2 hrs) but were earlier than obtained after SC (T_max 6-10 hrs). Powders were less efficiently dosed to the lung lobes after insufflation compared with instillates (14.7 ± 10.5 vs. 60.1 ± 10.6%), resulting in bioavailabilities ranging from 5 to 33%. Bioavailability after SC was 11.0 ± 7.0% and 95.3 ± 7.9% (n = 6) for the low and high doses, respectively.     

Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man

The pharmacodynamics of a racemic mixture of ketamine R,S (±)-ketamine and of each enantiomer, S(+)-ketamine and R(–)-ketamine, were studied in five volunteers. The median frequency of the electroencephalogram (EEG) power spectrum, a continuous noninvasive measure of the degree of central nervous system (CNS) depression (pharmacodynamics), was related to measured serum concentrations of drug (pharmacokinetics). The concentration-effect relationship was described by an inhibitory sigmoid E_max pharmacodynamic model, yielding estimates of both maximal effect (E_max) and sensitivity (IC₅₀) to the racemic and enantiomeric forms of ketamine. R(–)-ketamine was not as effective as R,S(±)-ketamine or S(+)-ketamine in causing EEG slowing. The maximal decrease (mean±SD) of the median frequency (E_max)for R(–)-ketamine was 4.4±0.5 Hz and was significantly different fromR,S (±)-ketamine (7.6 ±1.7 Hz) and S(+)-ketamine (8.3±1.9Hz). The ketamine serum concentration that caused one-half of the maximal median frequency decrease (IC₅₀) was 1.8±0.5g/mL for R(–)-ketamine; 2.0±0.5 g/mL for R,S(±)-ketamine; and 0.8±0.4 g/mL for S(+)-ketamine. Because the maximal effect (E_max) of the R(–)-ketamine was different from that of S(+)-ketamine and R,S(±)-ketamine, it was not possible to directly compare the potency (i.e., IC₅₀) of these compounds. Accordingly, a classical agonist/partial-agonist interaction model was examined, using the separate enantiomer results to predict racemate results. Although the model did not predict racemate results well, its failure was not so great as to provide clear evidence of synergism (or excess antagonism) of the enantiomers.This work was supported in part by a Starter Grant from the American Society of Anesthesiologists, the Biomedical Research Support Grant NIH 2S07RR5353-20, 1981, (P.F.W.); and NIH and NIA Research Grants NS-17956 and AG03104 (D.R.S., A.J.T., L.B.S). The research fellowship of Dr. Schüttler was made possible by a NATO Foundation Grant (300-402-511-3), awarded by the German Academic Exchange Service. This study is part of Dr. Schüttler's Habilitation Thesis for the Faculty of Medicine at the University of Bonn, West Germany. Dr. Verotta is a fellow of the program of advanced training established by EEC and Regione Lombardia on leave of absence from Mario Negri Institute of Pharmacological Research, Milan, Italy.