Effects of low and high density lipoproteins on renal cyclosporine A and cyclosporine G disposition in the isolated perfused rat kidney.

PURPOSE: This study investigated the effects of low (LDL) and high density lipoproteins (HDL) on renal cyclosporine A (CsA) and cyclosporine G (CsG) disposition in the isolated perfused rat kidney model. METHODS: Kidneys were perfused with CsA or CsG in perfusion medium containing 6% protein, bovine serum albumin only (BSA) (Control), LDL (200 mg/dl) and BSA, or HDL (200 mg/dl) and BSA. In vitro protein binding studies were conducted with CsA and CsG in the same media. RESULTS: The unbound fractions (fu) of CsA and CsG were significantly reduced with LDL and HDL in the perfusion media. In the presence of LDL, fu for CsA and CsG was 3.9% and 5.9%, respectively. With HDL, fu was 2.1% for CsA and 1.8% for CsG. fu for the controls was 14.7% for CsA and 11.9% for CsG. Renal clearance (CLR) of CsA and CsG was significantly reduced when perfused with perfusion medium containing LDL and HDL. LDL and HDL had similar effects on reducing CsA and CsG CLR, and were approximately four-fold lower when compared to controls (approximately 0.006 Vs. 0.023 ml/min). Renal CsA and CsG tissue (whole organ, cortex and medulla) concentrations were lower than corresponding controls when perfused with LDL or HDL. CONCLUSIONS: The interaction of CsA and CsG with LDL and HDL significantly reduced the CLR and extent of renal tissue distribution of both compounds.

Factors affecting pharmacists' selection of rural or urban practice sites in Nebraska.

A questionnaire was used to determine why pharmacists in Nebraska chose urban or rural practice sites and to help the University of Nebraska College of Pharmacy encourage students to consider rural practice. Questionnaires were mailed to 1427 Nebraska pharmacists to gather data about their practice, job satisfaction, location of rearing, location of spouse's rearing, and prepharmacy and clerkship training. Usable responses were sorted into those from urban pharmacists (residing in Omaha and Lincoln and their suburban areas) and those from rural pharmacists (all others). Of the 689 usable responses, 315 (45.7%) were from urban pharmacists and 374 (54.3%) were from rural pharmacists. Of the rural pharmacists, 93% [corrected] grew up in communities of fewer than 100,000 people and 60% grew up in communities of fewer than 5,000 people. Respondents cited income potential, desirability of practice site, influence of spouse and family, and quality of children's schools as factors that most influenced their choice of practice site. Based on the survey results, the University of Nebraska College of Pharmacy took actions to recruit students from rural communities and increase students' exposure to rural practice settings. Pharmacists who were reared or trained in rural areas were more likely to practice in rural Nebraska than pharmacists who had only urban experience.

Comparative bioavailability characteristics of commercial quinidine polygalacturonate and sulfate tablets.

This study compared the relative bioavailability characteristics of quinidine polygalacturonate (QP) and quinidine sulfate (QS) after oral administration of commercial tablets and a liquid form prepared from crushed tablets in 13 healthy adult male volunteers. Each subject received the following four single-dose treatments in a randomized, crossover manner with a one-week washout period between treatments: 400 mg QS liquid, two 200-mg QS tablets, 550 mg QP liquid, and two 275-mg QP tablets. All four treatments were equivalent in terms of the dose of quinidine base. Multiple serum samples and two 24-hour urine specimens were collected over 24 and 48 hours, respectively, and assayed for quinidine with a specific HPLC assay method. For the absorption and disposition parameters measured (maximum serum concentration, time to reach maximum concentration, area under the concentration-time curve [0-48 hours], absorption and elimination rate constants, absorption and elimination half-lives, apparent total body clearance, apparent volume of distribution, and dose fraction excreted in the urine) no significant differences were observed for any of the parameters among the four treatments (p greater than 0.05). The results of the present investigation demonstrated that QP and QS produced identical serum quinidine concentration-time curves when given in the form of a tablet or liquid. The clinical implications of these observations with respect to the dosing of QP are discussed.

Phenytoin disposition in the pregnant rat. Dose-dependent studies and salicylate effects.

Studies were conducted in 19-day gestation Sprague-Dawley rats to investigate the dose dependency and effects of salicylate coadministration on phenytoin disposition during pregnancy. After iv loading doses of both drugs, concurrent iv infusions of 75.6, 151.2, or 302.4 micrograms/min/kg of 14C-phenytoin and 65, 130, or 195 micrograms/min/kg of salicylate were administered for 180 min. Maternal plasma, fetal plasma, and whole fetus samples were obtained during the infusions, and maternal tissue (heart, skeletal muscle, fat, liver, and brain) and cerebrospinal fluid specimens were collected at the termination of drug administration. All samples were assayed for phenytoin and p-hydroxydiphenylhydantoin by liquid scintillation counting following separation by TLC. Systemic and intrinsic phenytoin clearance, which averaged 12 and 41.5 ml/min/kg, respectively, for the three phenytoin infusions, were both dose independent, and were unaltered by the three salicylate treatments. Similarly, the maternal tissue-to-plasma concentration ratios for phenytoin and p-hydroxydiphenylhydantoin were dose and/or concentration independent following the three phenytoin infusions, and were also not affected by salicylate coadministration. Additionally, the fetal distribution ratios for whole fetus-to-maternal plasma and whole fetus-to-fetal plasma were also invariant for the three phenytoin infusions and salicylate treatments. The results showed that the maternal and fetal disposition of phenytoin was dose and concentration independent and unaltered by salicylate coadministration with the dosages studied.

Further observations on the disposition characteristics of salicylic acid in analbuminemic rats.

The disposition characteristics of salicylic acid (SA) were investigated in analbuminemic rats after intravenous bolus injection of 10 and 173 mg kg-1 of SA to study the effects of plasma protein binding on drug disposition. Following the administration of 10 mg kg-1 of SA, total body SA clearance (CL) was markedly faster and its apparent volume of distribution (Vd) significantly greater in the analbuminemic rats in comparison to the controls. Further, the apparent elimination rate constant (kj) was two-fold greater and the corresponding elimination half-life (t 1/2) shorter in the rats with low plasma albumin. Whole body autoradiograms obtained following the administration of 14C-salicylic acid demonstrated that the tissue distribution of SA was greater in the analbuminemic rats which was in agreement with the larger Vd observed in this group of rats. After the administration of 173 mg kg-1 of SA, no differences in CL, Vd, kk or t 1/2 were noted between the analbuminemic and control rats. Dose-dependent SA disposition was observed in both the analbuminemic and control rats with the effects being more pronounced in the rats with low plasma albumin. The results suggested that the disposition characteristics of SA were markedly altered in the presence of low plasma albumin concentrations due to reduced plasma SA protein binding.

Radiolabeled 9- or 10-monoiodostearic acid and 9- or 10-monoiodostearyl carnitine--I. Synthesis and purification.

The purpose of this investigation was to synthesize and purify radiolabeled 9- or 10-monoiodostearyl carnitine for potential use as a perfusion and metabolic imaging agent for the heart. Oleic acid was iodinated via a free radical addition reaction of HI across the double bond to give 9- or 10-monoiodostearic acid which in turn was esterified with carnitine. The identity of 9- or 10-monoiodostearic acid and 9- or 10-monoiodostearyl carnitine was determined using nuclear magnetic resonance (NMR), infrared (i.r.), ultraviolet (u.v.), and mass spectroscopy. The purity of the fatty acid and carnitine ester was established by thin layer chromatography. 9- or 10-Monoiodo[125I]stearic acid and 9- or 10-monoiodo[125I]stearyl carnitine were synthesized via the isotopic exchange of 125I for cold iodine bonded to 9- or 10-monoiodostearic acid and 9- or 10-monoiodostearyl carnitine.

Amiodarone pharmacokinetics. III. Influence of thyroid dysfunction on amiodarone absorption and disposition.

Hypothyroid, hyperthyroid and euthyroid rats were given 45 or 80 mg/kg i.v. or 100 mg/kg p.o. of amiodarone hydrochloride to determine the effects of thyroid dysfunction on the absorption and disposition characteristics of amiodarone. Serial blood samples were obtained for 48 hr and assayed for amiodarone and desethylamiodarone by high-performance liquid chromatography. In the hypothyroid rats, reductions in amiodarone clearance (CL) of 73% (26.9-7.3 ml/min/kg) and 61% (18.7-7.3 ml/min/kg) were observed with the 45- and 80-mg/kg i.v. bolus doses, respectively. Accompanying the decreases in CL were increases in the terminal disposition half-life (T1/2 gamma), 89% (18-34 hr) with the 45-mg/kg dose and 185% (20-57 hr) after the 80-mg/kg dose. The steady state (Vss) and apparent (Vd) volumes of distribution were smaller at the lower dose but were invariant after administration of the larger dose. Furthermore, the central compartment volume was not altered. In the hyperthyroid rats, a 67% increase in CL (12.8-21.4 ml/min/kg) and 75 to 80% increases in Vss (15.5-27.1 liters/kg) and Vd (25.0-44.8 liters/kg) were observed with the 45-mg/kg of amiodarone dose. However, no changes in CL, Vd and Vss were seen with the 80-mg/kg dose. Furthermore, gamma, T1/2 gamma and central compartment volume were not altered in the hyperthyroid rats. The effects of thyroid dysfunction on the p.o. bioavailability characteristics of amiodarone were minor. These studies demonstrated that the disposition kinetics of amiodarone are altered in hypo- and hyperthyroidism.

Amiodarone pharmacokinetics. II. Disposition kinetics following subchronic administration in rats.

A 30 mg kg-1 intravenous bolus of 14C-amiodarone (19 microCi kg-1) was given to male Sprague-Dawley rats pretreated with 0 (vehicle), 25 or 100 mg kg-1 day-1 of amiodarone HCl orally for 37-42 days to determine the effects of dose and duration of administration on the disposition kinetics of amiodarone. Serial blood samples and total urine were collected over 48 hours and assayed for 14C-amiodarone by liquid scintillation counting following separation by HPLC. In all three groups, the blood 14C-amiodarone concentration-time curves declined bioexponentially with terminal half-lives (t1/2 beta) ranging from 14-22 hours. No differences in beta, t1/2 beta, or central compartment volume (Vc) were observed between the three groups of rats. In the rats pretreated with 100 mg kg-1 day-1 of amiodarone HCl for 5-6 weeks, amiodarone clearance (CL) and steady state volume of distribution (Vss) were reduced 52 per cent (12.2 to 5.9 ml min-1 kg-1) and 41 per cent (11.73 to 6.97 l kg-1), respectively. At the lower amiodarone daily dose, no changes in CL or Vss were observed. Negligible levels of radioactivity were detected in the urine. Amiodarone accounted for approximately 30-40 per cent of the total radioactivity in each blood specimen. This study demonstrated that CL and Vss were dose-dependent, and that beta, t1/2 beta and Vc were dose-independent. The results further suggested that the disposition kinetics of amiodarone were independent of the duration of drug administration.

Amiodarone pharmacokinetics. I. Acute dose-dependent disposition studies in rats.

Single intravenous bolus doses of amiodarone hydrochloride of 30, 60, 90 and 120 mg/kg were administered to male Sprague-Dawley rats to determine the effects of dose on amiodarone pharmacokinetics. Serial blood samples and total urine were collected over 48 hr and assayed for amiodarone and desethylamiodarone by HPLC. The blood amiodarone concentration-time curves for the four doses were best described by a triexponential equation with terminal half-lives (t1/2 gamma) ranging from 17 to 20 hr. Over the dose range studied, no changes in gamma, t1/2 gamma, or central compartment volume (Vc = 1.2-1.4 L/kg) were observed. On the other hand, reductions in amiodarone clearance (CL) and steady-state volume of distribution (Vss) of 44% (17.7 to 10.0 ml/min per kg) and 50% (16.4 to 8.2 L/kg), respectively, were noted as the dose of amiodarone increased. The conversion of amiodarone to desethylamiodarone (fm) was dose-independent and amounted to approximately 10% of each amiodarone dose. No amiodarone or desethylamiodarone was detected in the urine of any of the treated animals. The blood-to-plasma concentration ratio of amiodarone was concentration-independent and therefore did not account for the dose-dependent changes in Vss and CL observed. The data suggested that the dose-dependent changes noted were due to an alteration in the volume (s) of the peripheral tissue compartment(s).

Sorption of amiodarone to polyvinyl chloride infusion bags and administration sets.

The loss of amiodarone from i.v. admixtures to flexible polyvinyl chloride (PVC) infusion bags and i.v. administration sets was studied. Admixtures containing amiodarone hydrochloride 600 micrograms/mL and either 5% dextrose injection or 0.9% sodium chloride injection were stored at room temperature in glass bottles (both with and without contact of the drug solution with the rubber bottle closure), in flexible PVC bags, or in rigid PVC bottles. After 120 hours, the contents of each flexible PVC bag were emptied and replaced by methanol, which was allowed to remain in the bag for an additional 120 hours and was then analyzed for amiodarone content. To determine availability of amiodarone after infusion through a 1.8-m PVC i.v. administration set, solutions stored in glass containers were run through the set at 0.5 mL/min for 90 minutes. Samples of drug solutions were collected at appropriate intervals and analyzed by a stability-indicating high-performance liquid chromatography (HPLC) assay. Admixtures containing 0.9% sodium chloride injection were not stable; visual incompatibility was evident after 24 hours of storage in glass bottles, and no further testing was performed. In admixtures containing 5% dextrose injection that were stored in 50-mL flexible PVC bags, 60% of the initial amiodarone concentration remained after 120 hours; approximately half of the lost drug was recovered with the methanol. In effluent collected from the PVC administration set, 82% of the initial amiodarone concentration remained. Amiodarone concentrations did not decrease appreciably, after storage in glass or rigid PVC bottles, indicating that drug loss was probably affected by the plasticizer, di-2-ethylhexyl phthalate.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of ibuprofen on the disposition kinetics of phenytoin in pregnant rats.

The effects of ibuprofen on maternal phenytoin pharmacokinetics and fetal phenytoin acquisition were investigated in 19-day gestation Sprague-Dawley rats. A 5 mg kg-1 bolus injection of 14C-phenytoin was given with and without (control) pretreatment with 12.5 mg kg-1 of ibuprofen. Maternal plasma and fetal whole body samples were obtained at various times after the phenytoin bolus and evaluated simultaneously using a three-compartment maternal-fetal model. Ibuprofen pretreatment increased the maternal plasma clearance of phenytoin about three-fold and the overall apparent volume of distribution almost four-fold. No changes in the volume of the maternal central compartment or terminal first-order disposition rate constant were observed. Additionally, the maternal-to-fetal clearance of phenytoin was not altered in the ibuprofen-treated rats. No differences in the apparent fetal volume of distribution or areas under the fetal phenytoin concentration-time curves were observed between the control and ibuprofen-treated rats. The results of this study were consistent with ibuprofen-induced alterations in organ and tissue blood perfusion and demonstrated that, while the maternal disposition kinetics of phenytoin were altered by sodium ibuprofen coadministration, the maternal changes did not affect the extent of fetal exposure to phenytoin.

Rapid liquid chromatographic assay for the determination of amiodarone and its N-deethyl metabolite in plasma, urine, and bile.

A rapid high-performance liquid chromatographic assay was developed for the determination of amiodarone (1) and its N-deethyl metabolite (desethylamiodarone, 2) in plasma, urine, and bile. Analysis was performed on a C18 reversed-phase column and precolumn using a mobile phase consisting of methanol:water:58% ammonium hydroxide (94:4:2) delivered at a flow rate of 1.5 mL/min. The eluant was monitored at 244 nm. Under these conditions, 1, 2, and the internal standard eluted with retention times of 5.5, 4.6, and 6.8 min, respectively. Samples (100 microL) of plasma were prepared by precipitating the plasma proteins with acetonitrile containing the internal standard and injecting an aliquot of the supernatant directly onto the column. Samples (100 microL) of urine and bile were prepared for injection by acidifying the sample with concentrated HCl and then extracting the mixture with six volumes of 2,2-dimethoxyproprane. The recovery of 1 and 2 from plasma was virtually complete. The recovery from urine and bile was 80-90% for 1 and 60-65% for 2. The limit of sensitivity of both compounds in plasma was 100 ng/mL. For urine and bile, the detection limits were 1 and 5 micrograms/mL, respectively. Over the plasma concentration range of 0.1-10.0 micrograms/mL, the within-day CV ranged from 1 to 10% for 1 and from 1 to 8% for 2. The between-day CV ranged from 2 to 12% and from 1 to 17% for 1 and 2, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum disopyramide concentrations and suppression of ventricular premature contractions.

Serum disopyramide determinations and 24-hour Holter monitoring were performed in 20 cardiac subjects with ventricular premature contractions (VPCs) after the first, seventeenth, and thirty-seventh doses of disopyramide, 100 mg (10 subjects; low-dose group) or 200 mg (10 subjects; high-dose group) every 6 hr for 10 days to assess the ability of single- or first-dose data to predict serum disopyramide concentrations at steady state and the relationship between steady-state serum disopyramide concentrations and VPC suppression. Control Holter recordings were made for 48 hr in each subject. There were strong correlations in both groups between data for the AUC over 0 to 6 hr for the first dose (AUC60) and average (C ss) and trough (C min) steady-rate serum disopyramide concentrations after the seventeenth and thirty-seventh doses and the two combined. C ss and C min were related to AUC60 by the following expressions for both dosage groups: C ss = 0.22 AUC60 + 0.90 and C min = 0.20 AUC60 + 0.70. There were good correlations between 6-hr serum disopyramide concentration after the first dose and C ss and C min. There was strong correlation between overall average steady-state serum disopyramide concentration and suppression of VPC frequency. The relationship between VPC suppression and overall average trough serum disopyramide concentration at steady state, on the other hand, was weak.

Effect of antacid on the bioavailabiity of lithium carbonate.

The effect of an antacid on the bioavailability of lithium carbonate was determined in six healthy men in a crossover study. The volunteers were given single 300-mg doses of lithium carbonate alone and with 30 ml of an antacid containing aluminum and magnesium hydroxides with simethicone. Blood samples were collected at various times for 0-24 hours after each dose. The plasma samples were analyzed for lithium using a spectrophotometer, and bioavailability variables were calculated from plasma lithium concentration-time curves. There were no significant differences in peak plasma lithium concentration, time to peak concentration, area under the concentration-time curve from 0 to 24 hours, first-order absorption rate constant, and first-order elimination rate constant between the two treatments. Concurrent administration of antacids and lithium carbonate should not affect lithium blood concentrations.

Effects of salicylate on maternal and fetal phenytoin pharmacokinetics in rats.

The effects of salicylate on maternal and fetal phenytoin pharmacokinetics were investigated in 19-day pregnant Sprague-Dawley rats after a 5 mg/kg bolus injection of 14C-phenytoin was given with and without (control) prior salicylate (75 mg/kg) treatment. Maternal plasma and fetal whole body samples were obtained at various times after the phenytoin bolus and evaluated simultaneously using a three-compartment maternal-fetal model. An increase in maternal plasma phenytoin clearance, central compartment volume, and over-all apparent volume of distribution with no change in the terminal first order hybrid disposition rate constant (beta) was observed in the salicylate-treated rats. These dispositional changes were consistent with the elevations in serum free or unbound phenytoin concentrations observed in vitro in the presence of salicylate. The maternal-to-fetal clearance of phenytoin was faster in the rats given sodium salicylate. However, the maternal-to-fetal (k13) as well as fetal-to-maternal (k31) phenytoin transfer rate constants were not altered by the salicylate treatment. Additionally, no changes in the apparent fetal phenytoin volume of distribution or area under the fetal phenytoin concentration-time curves were seen. Although the maternal pharmacokinetics of phenytoin were altered by sodium salicylate co-administration, the extent of fetal exposure to phenytoin did not change.

Comparative disposition kinetics of two diastereomeric pairs of cinchona alkaloids in the dog.

The comparative disposition kinetics of quinidine, quinine, cinchonine , and cinchonidine were investigated in five male, mongrel dogs after intravenous bolus injections of a 9.2-mmol/kg dose of each alkaloid base. Blood and plasma specimens were obtained at various times up to 6 h postdose and assayed for quinidine and quinine with a TLC-fluorometric procedure and for cinchonine and cinchonidine by HPLC. The plasma alkaloid concentration-time data were analyzed by weighted, nonlinear least-squares regression analysis to obtain the central compartment volume (Vc), disposition rate constants (alpha and beta), and corresponding half-life values (t1/2). Total body clearance (CL) and apparent volume of distribution (Vd) were estimated by nonparametric analysis. In this study, the highest plasma alkaloid concentrations were reached with quinidine and the lowest concentrations with the quinidine congener, cinchonine . The other congeneric pair, quinine and cinchonidine , exhibited plasma alkaloid concentrations that were comparable and intermediate to those of quinidine and cinchonine . With cinchonine and cinchonidine , the plasma and blood concentration-time curves were virtually superimposable. However, with quinidine and quinine, the plasma alkaloid concentrations of these diastereomers were approximately twice the corresponding blood concentrations. The total body clearance rate of quinidine was significantly slower than quinine and cinchonine clearance. No difference in clearance was observed between cinchonine and cinchonidine . The beta and t1/2 beta for quinidine were significantly smaller and larger, respectively, than the corresponding values obtained with the other alkaloids. No significant differences in alpha or Vc and Vd were found between and within the two diastereomeric pairs of alkaloids. The differences in disposition kinetics observed in this study were attributable to an interaction of stereochemical and 6'-methoxy group substitution effects.

Apparent dose-dependent oral absorption of cyclosporin A in rats.

The oral absorption of cyclosporin A (CyA) was studied in rats after 6, 12, 18, and 23 mg kg-1 doses were given in an olive oil solution to determine if CyA absorption from the gastrointestinal tract was dose-dependent. Using serial blood samples obtained at various times after the respective doses, analysis of the resultant blood CyA concentration-time curves suggested that the rate of CyA absorption for all four doses was an apparent zero-order process. Moreover, the rate of CyA absorption appeared to be dose-dependent, increasing as the dose of CyA increased. Similarly, the extent of CyA absorption (F) also exhibited dose-dependent characteristics in this study. F increased from 0.13 after the 6 mg kg-1 dose to 0.22 with the 18 and 23 mg kg-1 doses (p less than 0.05). In the present investigation, the observed values for the duration of drug absorption (T), terminal first-order rate constant (beta) and corresponding elimination half-life (T 1/2 beta) of approximately 4-5 h, 0.030 h-1 and 21-28 h, respectively, were similar for all CyA doses. Moreover, no difference in beta was observed after oral or intravenous drug administration. Absorption lag times of 1-2 h were found. The results suggested that the dose-dependent absorption of CyA observed in the present study was possibly related to the effects of olive oil on gastric emptying and that CyA might be unstable in the gastric fluids and/or metabolized by the gastric mucosa.

Stability of nitroglycerin in intravenous admixtures.

The stability of nitroglycerin in intravenous admixtures was studied. Admixtures containing nitroglycerin 400 micrograms/ml and each of seven injectable drugs in concentrations used clinically were prepared in triplicate in 5% dextrose and 0.9% sodium chloride injections. Admixtures were stored in glass bottles at room temperature for 24 hours in the upright position and then for 24 hours in the inverted position to ensure contact of the solution with the rubber stopper of the container. At 0, 24, and 48 hours, samples of each admixture were assayed by high-performance liquid chromatography for nitroglycerin concentration. The pH of one randomly chosen bottle of each admixture was measured at 0, 24, and 48 hours. A significant loss of nitroglycerin potency at 48 hours was observed only in admixtures containing phenytoin; in these solutions, a 9% decrease in initial nitroglycerin concentration was noted. Phenytoin crystallization was present in all phenytoin admixtures by 24 hours. Compared with initial values, no significant differences in the pH values of any admixture samples assayed at 24 and 48 hours were noted; however, admixtures containing phenytoin had the most alkaline pH values. Under the conditions studied, nitroglycerin concentrations remained above 90% of their initial values for 48 hours in all tested admixtures; however, phenytoin crystallization limits the stability of phenytoin admixtures.

Relationship between saliva and serum quinidine concentrations and suppression of ventricular premature beats.

Saliva and serum quinidine concentrations were determined in six cardiac patients after twice-daily dosing with 324 or 648 mg quinidine gluconate and the relationship of these concentrations to the degree of suppression of ventricular premature beats (VPB) was evaluated. Mixed saliva and corresponding serum samples were obtained at various times after the 1st, 9th, and 19th doses. With serum quinidine concentrations ranging from 0.05 to 0.83 micrograms/ml after the first dose, the average saliva/serum ratios for quinidine varied between 0.25 and 1.35 (0.54 +/- 0.43). At steady state with the serum quinidine concentrations ranging between 0.36 and 3.35 micrograms/ml, the average saliva/serum ratios ranged from 0.27 to 1.79 (0.81 +/- 0.72) and from 0.19 to 1.84 (0.90 +/- 0.85) for the 9th and 19th doses, respectively. The interpatient variations in the saliva/serum ratio were large for the three doses (approximately 90%). On the other hand, the intrapatient variations were smaller and diminished with each succeeding sampled dose (from 31 to 18 to 12% for the 1st, 9th, and 19th doses, respectively). Moreover, the value for the quinidine saliva/serum ratio for a given patient was similar for all three doses. No significant correlation between the extent of VPB suppression and the concentrations of quinidine in the saliva or serum was observed. The data suggest that salivary quinidine concentrations may be clinically useful to monitor serum drug concentrations in a given patient. However, the relationship between saliva and serum quinidine concentrations and suppression of VPB measured by Holter monitoring is not clear-cut.

Effect of caffeine on the oral absorption and disposition of quinidine.

The effect of caffeine on the oral absorption and disposition of quinidine was assessed in nine healthy men. Single 300-mg doses of quinidine sulfate were given by mouth in the absence and presence of caffeine in a crossover study. In the caffeine-treatment phase, 1 g of caffeine was given per day in divided doses for one week before the administration of a second 300-mg quinidine sulfate dose. Blood samples were collected at various times for 24 hours after drug administration, and the sera were assayed for quinidine. Urine specimens were also analyzed for quinidine. No differences were found in the quinidine absorption and disposition constants between the control and caffeine-treated phases, using a nonlinear, least-squares regression analysis of the serum quinidine concentration-time curves and standard blood and urine bioavailability test methods. The hypothesis proposed by previous investigators that quinidine disposition may be altered by caffeine-inducible hepatic microsomal enzymes was not supported by these data. Caffeine treatment at a daily dose of 1 g per day for one week had no apparent effect on the absorption or disposition of quinidine after a single 300-mg oral dose of quinidine sulfate in healthy men.