Paul A. Kramer

Toxic interaction between acetazolamide and salicylate: Case reports and a pharmacokinetic explanation

Two elderly patients, who were chronically receiving aspirin, developed lethargy, incontinence, and confusion after dosing with acetazolamide. Unbound plasma acetazolamide concentrations were elevated and plasma protein binding was reduced, suggesting an interaction with aspirin. In vitro studies demonstrated a concentration‐dependent effect of salicylate on acetazolamide binding to serum proteins. At a therapeutic serum acetazolamide level of 8.0 µg/ml, the unbound percentage of acetazolamide in serum was 3.3% and increased to 11.0% and 30.0%, with serum salicylate levels of 200 and 386 µg/ml, respectively. Furthermore, the apparent association constant of acetazolamide for binding to serum proteins was decreased by 58% and 86% of its control value at these respective salicylate concentrations. The maximal binding capacity of serum for acetazolamide was not affected by salicylate. Pharmacokinetic studies in four volunteers showed that the plasma protein binding and renal clearance of acetazolamide were significantly reduced during chronic salicylate dosing. Salicylate appears to competitively inhibit the plasma protein binding of acetazolamide and simultaneously to inhibit acetazolamide renal tubular secretion. Caution is advised when acetazolamide and salicylate are used concurrently.

Furosemide pharmacokinetics in very low birth weight infants

The pharmacokinetics of furosemide were studied longitudinally during long-term administration in 10 very low birth weight infants with bronchopulmonary dysplasia. Mean birth weight of the infants was 829 +/- 217 g, mean gestational age at birth was 26.6 +/- 2.9 weeks, and mean postnatal age at the start of therapy was 2.4 +/- 1.0 weeks. Serial determinations of furosemide pharmacokinetic parameters were performed during 2 weeks to 3 months of long-term therapy. Plasma half-life was prolonged in infants less than 31 weeks postconceptional age (gestational + postnatal age), frequently exceeding 24 hours. All infants less than 29 weeks postconceptional age whose dosing schedule was once every 12 hours accumulated furosemide to potentially ototoxic levels. Furosemide renal clearance increased and plasma half-life decreased in association with increasing postconceptional age. Furosemide secretory clearance was very low in patients less than 31 weeks postconceptional age, resulting in a reliance on glomerular filtration to deliver drug to its main site of action within the lumen of the loop of Henle. Thus elevated plasma levels may be required to ensure adequate luminal delivery and adequate diuresis in these infants with low secretory clearance. Nevertheless, the current dosing schedule (once every 12 hours) of furosemide should be modified to once every 24 hours in infants of low postconceptional age to avoid possible toxic effects.

Imipramine Disposition in Alcoholics

The disposition of orally administered imipramine (IMI) was studied in 11 depressed alcoholic and 12 depressed nonalcoholic male inpatients. Subjects received 50 mg three times daily for at least 10 days to ensure steady state. Following a temporary discontinuation of therapy, several blood samples were drawn over a 40-hour period. Imipramine, desipramine, and their 2-hydroxylated metabolites were measured in plasma using a high performance liquid chromatography assay. Eight hours following the last dose, alcoholics had significantly lower IMI (50 ± 41 versus 106 ± 46 ng/ml; p<0.005) and 2-hydroxyimipramine (12.8 ± 7.5 versus 22.6 ± 9.8 ng/ml; p< 0.01) levels than controls. The mean terminal half-lives in the two groups were nearly identical (16.3 ± 6.7 hours in alcoholics versus 17.1 ± 5.4 hours in controls). Beck Depression Inventory scores were significantly reduced during IMI therapy (p<0.001) in the nonalcoholic controls, whereas no change was observed in the alcoholic group. These results are consistent with either a decrease in oral bioavailability of IMI in alcoholics or, assuming complete absorption, an increase in intrinsic clearance of 2.5 fold (2444 ± 1151 versus 986 ± 438 ml/min; p<0.005) over the clearance found in control subjects. The latter seems a more likely result of chronic ethanol intake. The fact that lower levels of IMI in the alcoholic group were accompanied by a lack of efficacy in relieving depressive symptomatology suggests that whether through an effect on bioavailability or intrinsic clearance, ethanol consumption is an important consideration when recommending tricyclic therapy.

Kinetic discrimination of three sulfamethazine acetylation phenotypes

The relationship between sulfamethazine disposition kinetics and acetylator phenotype was studied in 19 healthy subjects. Various kinetic parameters for sulfamethazine and its N4‐acetylated metabolite were determined after a dose of a rapidly absorbed oral solution. When plotted on a frequency distribution histogram, the results exhibited a well‐defined trimodal pattern for acetylation clearance values and overall elimination or metabolic rate constants. These data were consistent with the well‐recognized acetylation polymorphism for sulfamethazine, except that they clearly subdivided the previously acknowledged “fast” acetylator mode into intermediate and rapid acetylator groups. The apparent distribution volume and renal clearance for sulfamethazine and acetylsulfamethazine did not differ significantly among the 3 phenotypes. Of special interest was the observation that rapid acetylators initially produce much greater amounts of acetyl metabolite than intermediate acetylators. The potential clinical implications of identifying rapid and intermediate acetylators are discussed in view of evidence showing that acetyl metabolites may be pharmacologically active or function as intermediates in toxic metabolic pathways.

Tetracycline absorption in elderly patients with achlorhydria

Five elderly achlorhydric patients and five controls took 250 mg tetracycline as a capsule or as an oral solution. Venous blood samples drawn during the 12‐hr period following administration and urine collected for 72 hr post‐dosing were assayed fluorometrically for tetracycline. There were no differences between the two groups in either rate or extent of tetracycline absorption. The mean apparent first‐order rate constant (ka) for absorption of drug from capsules was 0.58 ± 0.17 hr−1 for patients and 0.65 ± 0.21 hr−1 for controls. The mean extent of absorption for capsule dosage forms relative to an oral solution was 1.0 ± 0.20 for patients and 1.0 ± 0.24 for controls. Concurrent administration of 2 gm of sodium bicarbonate to 2 of the normal subjects resulted in no impairment of either the rate or extent of tetracycline absorption from capsules, suggesting that the effect of elevated gastric pH on tetracycline bioavailability may relate to formulation.

Pilocarpine Disposition and Salivary Flow Responses Following Intravenous Administration to Dogs

Oral doses of pilocarpine increase salivary flow rates in patients afflicted with xerostomia (dry mouth). This study examined the pharmacokinetics of and a pharmacodynamic response (salivation) to intravenous pilocarpine nitrate administration in dogs. Disposition was linear over a dose range of 225–600 µg/kg; plasma concentrations were 10–120 µg/L. Elimination was rapid and generally biphasic, with a terminal elimination half-life of approximately 1.3 hr. The systemic clearance of pilocarpine was high (2.22 ± 0.49 L/kg/hr) and its steady-state volume of distribution (2.30 ± 0.64 L/kg) was comparable to that of many other basic drugs. All doses of pilocarpine induced measurable submaxillary and parotid salivary flow rates which could be maintained constant over time. Cumulative submaxillary saliva flow was linearly related to total pilocarpine dose. Plasma pilocarpine concentration was linearly related to both steady-state and postinfusion submaxillary salivary flow rates.

Effects of hexagonal phase induction by dolichol on phospholipid membrane permeability and morphology

Abstract The effect of H 11 -phase induction by dolichol (DOL) (C 80–105 , 0–2 wt%) within the bilayers of multilamellar liposomes (MLV, DOPE:DOPC 2:1 or 3:1 w/w) on their permeability, lipid mixing and morphology was determined. Low-angle X-ray diffraction patterns were consistent with mixtures of bilaycr and H 11 phases, the latter increasing with increasing DOL or DOPE content and temperature. Efflux rate constants for 6-carboxyfluorescein (6-CF) from 2:1 DOPE:DOPC vesicles depended on temperature and DOPE/DOL content, increasing as much as 200-fold over DOL-free controls at 2% w/w DOL. Fluorescence resonance energy transfer assays detected lipid mixing with unlabeled target MLV. It was appreciable only when target MLV contained DOPE and increased with DOL content. Confocal scanning fluorescence microscopy was applied to study the morphological structure of fully-hydrated samples and field scanning electron microscopy the ultrastructure of cryo-stabilized samples. 3:1 DOPE/DOPC MLV, stable at pH 9.5, underwent rapid morphological changes at pH 7.4. Within minutes filaments formed and large areas of membrane surface became studded with 10–15 nm bumps and 5 nm holes, resembling in size and shape unilamellarly covered intcrlamellar micellar intermediates and interlamellar attachments (ILA) previously associated with H 11 -phase transitions. The filaments, seen in MLV with and without DOL, may represent extensions of IMI into coaxial assemblages of rod micellar intermediates (RMI). These phenomena may have implications for liposomal delivery of therapeutic peptides/proteins if they can be made to trigger the convective release of liposomal contents via controlled formation of ILA between adjacent lamellae of MLV.

Renal response to furosemide in very low birth weight infants during chronic administration.

Renal response to furosemide following initial and chronic doses was investigated in premature infants with bronchopulmonary dysplasia. Seven infants (mean birth weight = 890 +/- 216 g, mean gestational age at birth = 27.7 +/- 2.6 weeks, mean postnatal age at the start of diuretic therapy = 2.7 +/- 0.9 weeks) were studied. Twelve-hour urine collections were performed after the initial dose, and following chronic doses after 1 week and 3 weeks of therapy. Volume of each urine sample was measured and concentrations of furosemide, sodium and creatinine determined. Linear dose-response relationships were found between the logarithm of the urinary furosemide excretion rate and diuretic/natriuretic response (urine output and urinary sodium excretion rate). The furosemide excretion rate required to achieve midrange diuretic and natriuretic responses was significantly greater during chronic dosing than following initial doses, indicating a decrease in renal responsiveness to drug with sustained use. Increasing postconceptional age was associated with a decrease in initial responsiveness to furosemide. These data demonstrate that in premature infants renal sensitivity to furosemide decreases with chronic use as well as with increasing postconceptional age at the start of therapy. The decrease in renal sensitivity to drug with chronic use is of much greater magnitude, and appears to represent renal compensation for drug-induced diuresis and natriuresis.

Simultaneous determination of disulfiram and two of its dithiocarbamate metabolites in human plasma by reversed-phase liquid chromatography

Abstract A simple, sensitive, reversed-phase liquid chromatographic assay is reported for the simultaneous determination of disulfiram, diethyldithiocarbamate (DDC) and its methyl ester (MeDDC) in human plasma. A single-step extractive ethylation converts DDC to its ethyl ester which is then separated from endogenously produced MeDDC and parent disulfiram on an alkylphenyl column. The method is sufficiently sensitive (25 ng/ml) to permit DDC and MeDDC determination in patients receiving therapeutic doses of disulfiram.

Confocal imaging of peripheral regions of intact rat lungs following intratracheal administration of 6-carboxyfluorescein, FITC-insulin, and FITC-dextran.

AbstractPurpose. This study compared the pulmonary disposition of 3 structurally diverse probe molecules following their intratracheal (i.t.) administration to anesthetized rats. Methods. Following administration of 6-carboxyfluorescein (CF), FITC-insulin (FI) and FITC-dextran (FD), lungs were removed, inflated, perfused with a marker dye, and peripheral elements examined with confocal microscopy (CLSFM). Results. At 5 min most of each probe remained within airspaces; the remainder distributed to interstitium, capillaries, Type II cells, and macrophages. At 60 min disposition differed significantly among probes. The smallest (CF, 376 Da) had almost completely exited airspaces and was found primarily in extracellular interstitial spaces, often behind Type II cells. Disposition was consistent with both entry into peripheral lymphatics and association with peripheral fibers. FI and FD (6 and 10 kDa, respectively) were retained substantially longer within airspaces. In contrast to CF, FI appeared to localize along septal and peripheral fibers, but its disposition was inconsistent with the involvement of peripheral lymphatics. Conclusions. While all probes were ≤10 kDa, there was considerable disparity among both their rates of absorption and subsequent disposition within peri-alveolar elements. CLSFM appears to be a useful ancillary tool for studying the pulmonary absorption of drugs and macromolecules.