Quinidine saliva concentrations: absence of correlation with serum concentrations at steady state.

Serum and saliva quinidine concentrations were measured in eight subjects with cardiac arrhythmias on various dosage regimens. There was good correlation between serum and saliva quinidine concentration after a single dose, but there was no such relationship after repeated dosing. Comparison of the area under a hysteresis loop, obtained by plotting the saliva/serum quinidine concentration ratio as a function of serum quinidine concentration over a dosing interval, indicated an exponential increase with increasing mean serum quinidine concentration. Salivary quinidine concentration predictions based on the Henderson-Hasselbalch equation did not correlate with the serum quinidine concentration under the steady-state conditions. These data suggest that quinidine concentration in saliva is not a direct reflection of its serum concentration in cardiac patients on maintenance (steady-state) therapy and hence not useful for therapeutic drug monitoring.

Lidocaine and its active metabolites.

It has been shown that the antiarrhythmic and toxic effects of lidocaine may be in part dependent on its two active metabolites, monoethylglycylxylidide (MEGX) and glycylxylidide (GX). Presently available gas liquid chromatographic analytic methods require long and tedious steps or sophisticated equipment such as gas liquid chromatography-mass spectrometry. The assay method reported here with the use of high-performance liquid chromatography is rapid and allows accurate, precise determination of lidocaine, MEGX, and GX in biologic fluids. On the 3 patients studied extensively with the use of this assay, one patient had MEGX concentrations almost twice those of lidocaine. At 83% lidocaine potency, the contribution of MEGX in this patient was about 1.5 times that of lidocaine. The second patient studied on two consecutive days had a 20% increase in serum lidocaine concentration and an equivalent decrease in MEGX concentration on the second day. In the third patient lidocaine was stopped with a resulting half-life of 3.8 hr, which is consistent with previously reported values for patients on long-term lidocaine infusion. Urinary excretion of lidocaine and its metabolites is in agreement with previous work. These data suggest that much information still remains to be learned about the active metabolites of lidocaine as well as of lidocaine.

Digoxin pharmacokinetics in congestive heart failure.

The steady-state pharmacokinetics of oral digoxin in eight hospitalized patients was compared upon their admission with marked right-sided congestive heart failure and later when they were compensated. Large intersubject variations in the serum digoxin concentration profiles were observed. However, over a 24-hour dosing interval, digoxin concentrations in each patient studied during heart failure were either similar or higher than those observed when the patient became compensated. There were no significant differences in digoxin half-life of elimination between the two states. In contrast, the mean ratio of the fraction of digoxin dose absorbed to its apparent volume of distribution was increased by 37 per cent (P less than 0.05) in heart failure. Contrary to the prevailing notion, we found that the oral administration of supplemental doses of digoxin only on the basis of its reduced serum concentration in patients with congestive heart failure is unwarranted.

Influence of alcohol on the pharmacokinetics of diazepam controlled-release formulation in healthy volunteers.

Twelve normal volunteers were empanelled in an open-label, three-way crossover study to evaluate the influence of alcohol on the pharmacokinetics of controlled-release diazepam capsules. Each volunteer received one 15-mg diazepam controlled-release capsule alone, concomitantly with alcohol or followed by alcohol 2 hours later. The mean plasma concentration-time profiles following both alcohol treatments were superimposable on the profile from the control. The mean plateau concentrations were observed to endure from 2 through 12 hours in all cases. The mean +/- S.D. areas under the plasma concentration-time curves from time zero to infinity were similar indicating no difference in the extent of absorption of diazepam in the presence of alcohol. The harmonic mean elimination half-lives were also similar. Overall, the pharmacokinetics and the release properties of controlled-release diazepam capsule were not influenced by alcohol in normal volunteers.

Specific high-performance liquid chromatographic assay for nitroglycerin in dosage forms.

A specific assay for nitroglycerin dosage forms using high-performance liquid chromatography was developed. Sublingual nitroglycerin tablets are dissolved in 25 ml of water and injected directly into the chromatograph. Chromatographic conditions are: mobile phase, 60% methanol in water; flow rate, 2 ml/min; column, microparticulate reversed phase; and detection, 200 nm. The glyceryl mononitrate and dinitrate degradation products of nitroglycerin are separated from nitroglycerin and can be identified by altering the mobile phase composition of methanol.

Dihydroquinidine contamination of quinidine raw materials and dosage forms: rapid estimation by high-performance liquid chromatography.

Dihydroquinidine is a commonly encountered contaminant in quinidine raw materials. The USP allows 0-20% dihydroquinidine in quinidine products, but the assays used to quantitate dihydroquinidine have been lengthy or have required sophisticated equipment. The present method separates dihydroquinidine from quinidine and provides rapid, precise quantitation of both dihydroquinidine and quinidine. The clinical importance of dihydroquinidine contamination of quinidine dosage forms remains unanswered.

High-performance liquid chromatographic assay for benzocaine and p-aminobenzoic acid including preliminary stability data.

A high-performance liquid chromatographic assay was developed that separates and quantitates benzocaine and its primary degradation product, p-aminobenzoic acid. This method is rapid, sensitive, and specific. Preliminary stability data obtained with this method demonstrate its utility for this purpose.

Intestinal pH as a factor in selection of animal models for bioavailability testing.

Previous in situ studies showed that intestinal drug absorption is strongly influenced by intestinal pH. Three animal species considered for bioavailability testing were studied in situ to determine intestinal pH. Results from the rat and dog correlated well with results in humans, while results from the rabbit did not. The rabbit appears to be a poor candidate for attempted animal-human bioavailability correlations.

Drug absorption VII: influence of mesenteric blood flow on intestinal drug absorption in dogs.

Intestinal absorption of sulfaethidole and haloperidol was determined using an in situ canine intestinal preparation. Intestinal absorption of sulfaethidole was determined at three or four mesenteric blood flow rates in each dog, ranging from unaltered flow (100%) to no flow (0%). A relatively small change in absorption rate occurred when the splanchnic blood flow rate was decreased about 35%. Further reductions in mesenteric blood flow resulted in progressive impairment of sulfaethidole absorption. The simultaneous measurement of sulfaethidole intestinal disappearance and appearance in blood indicates that sulfaethidole disappearance is equivalent to absorption. Haloperidol absorption also decreased with decreased intestinal perfusion but differed from sulfaethidole in that membrane storage of haloperidol appeared to take place during its absorption.

Mechanism of fluorometric analysis of tetracycline involving metal complexation.

Tetracycline complexation with calcium and organic ligands was studied using fluorescence, circular dichroism, and solvent extraction methods. The results were used to interpret the mechanism of the commonly used fluorometric methods for the analysis of tetracycline in biological fluids. Tetracycline formed ternary calcium complexes with barbital sodium and L-tryptophan in alkaline solutions. The circular dichroism studies indicate that the calcium ion in these complexes is bound to the C-4 dimethylamino and the C-12a hydroxyl groups of tetracycline. These ternary complexes are strongly fluorescent and can be extracted easily into 1-butanol or ethyl acetate. Based on the characteristics of the ternary complexes and of the tetracycline degradation products, it is concluded that only the active form of tetracycline can be complexed and extracted for fluorescence analysis.

The effect of congestive heart failure on quinidine pharmacokinetics.

Quinidine is an effective antiarrhythmic agent whose therapeutic effects and toxicity have been related to its serum concentrations. Many patients with cardiac arrhythmias also suffer from congestive heart failure. It is well documented that congestive heart failure can reduce blood perfusion to many regions of the body, and could conceivably alter drug pharmacokinetics. A pharmacokinetic evaluation of two sets of quinidine data in congestive heart failure patients indicates that congestive heart failure reduced the rate of absorption and volume of distribution following oral or intramuscular administration of quinidine. Furthermore, the amount of quinidine absorbed following oral administration is reduced, but congestive heart failure does not appear to alter the elimination rate of quinidine. The interpretation of the data presented herein strongly suggests that the site of administration, extent of distribution, and rate of absorption must be considered when determining dosage regimens in congestive heart failure patients since normal dosages in these patients result in abnormally high serum quinidine concentrations.

Clofibrate pharmacokinetics: effect of elevation of plasma-free fatty acids.

The pharmacokinetics of rho-chlorophenoxyisobutyrate (CPIB), the active metabolite of clofibrate were determined following intravenous administration in the rat. Serum CPIB concentrations were measured using an new TLC-GLC method. The results agree favourably with pharmacokinetics in human subjects after oral administration of clofibrate. Both clofibrate and free fatty acids (FFA) are extensively bound to circulating plasma proteins. When plasma FFA were elevated to about 2,000 muEq/1, the CPIB elimination half-life decreased form 19.3 h in controls to 7.3 h. Thus, elevation of FFA appears to significantly alter the pharmacokinetics of a highly bound drug.

Halofenate and clofibrate: mechanism of hypotriglyceridemic action in the rat.

Rats fed a fat-free diet containing no drug, 0.02% or 0.10% halofenate, or 0.25% clofibrate for 14 days were injected intravenously with equivalent amounts of either [2-3H]glycerol or [1(3)-3H]glycerol. Blood samples were collected at times up to 150 min after injection and serum triglycerides were isolated and assayed for radioactivity. Kinetic analysis of the serum appearance and clearance curves of 3H-labeled triglyceride permits estimation of serum total 3H-labeled triglyceride formation and triglyceride fractional turnover rates. The total amounts of 3H-labeled triglyceride formed from [2-3H] or from [1(3)-3H] glycerol in control-fed animals were very similar. Over 95% of the serum 3H-labeled triglyceride formed from either substrate circulated in a rapidly turning-over triglyceride pool (t1/2 = 8 min). Treatment with 0.10% halofenate or 0.25% clofibrate decreased labeling of serum triglycerides by 75-80% without increasing serum 3H-labeled triglyceride fractional turnover rates. Furthermore, both drugs decreased incorporation in vivo of 14C from [U-14C]glycerol into hepatic but not intestinal triglycerides without significantly decreasing incorporation of 14C into total phospholipids of either tissue. From these observations we suggest that, in the intact normal rat, sustained reduction of serum triglyceride levels produced by treatment with halofenate or clofibrate is due to inhibition of hepatic triglyceride formation.

Plasma protein binding of ceftriaxone.

1. The plasma protein binding characteristics of ceftriaxone, a new cephalosporin antibiotic, were determined in human, baboon, rabbit, dog and rat plasma. 2. The protein binding of ceftriaxone was similar and concentration-dependent in human, baboon, rabbit and rat plasma, being highly bound (90-95%) at low concentrations (less than 100 micrograms/ml) but considerably less bound (approx. 60%) at high concentrations (greater than 400 micrograms/ml). Binding in dog plasma was also concentration-dependent but much lower (approx. 25%) at lower concentrations (30 micrograms/ml) and virtually unbound (2%) at high concentrations (1 mg/ml) over a similar concentration range. 3. Binding of ceftriaxone to human plasma involved two sites: a high affinity-low capacity (saturable) site and a low affinity-high capacity site. Binding to dog plasma apparently was at a single, high affinity-low capacity site. 4. The pharmacokinetics of ceftriaxone in an animal species with binding characteristics similar to man (baboon), appear to be non-linear when based on total drug concentration and linear when based on the free drug concentration. In the dog, pharmacokinetic parameters did not change appreciably if calculated from total or free drug concentrations, due to the low protein binding.