Effect of nutritional status on organic anion clearance by the swine liver.

Hepatic dysfunction follows a wide range of insults. Impaired excretion of organic dyes such as bilirubin often occurs before other obvious clinical defects in metabolic processes. Indocyanine green (ICG) is excreted through pathways similar to those of bilirubin. To determine the effectiveness of ICG as a marker of hepatic dysfunction related to clinical malnutrition, pigs received 5 mg/kg ICG with simultaneous sampling from the hepatic vein, pulmonary artery, and aorta over 3 hours. Group I remained well nourished, group II was fasted to a weight loss equal to 20% of initial body weight, and group III was fasted to a 20% weight loss and then refed until the animals regained their initial weight. Both systemic and intrinsic hepatic clearance were depressed significantly with fasting but returned above baseline after refeeding. No significant difference appeared between systemic and intrinsic hepatic clearance. Extraction ratios were low in all groups. In outbred swine, ICG clearance reflects the function of hepatic organic anion excretion in vivo, and venous sampling reflects intrinsic hepatic clearance. The impairment of the carrier-mediated transport system is reversible with refeeding.

The effect of theophylline on estimated hepatic blood flow.

We observed the effect of aminophylline administration on estimated hepatic blood flow. Indocyanine green (ICG) 0.5 mg/kg was administered as an intravenous bolus dose before and after intravenous infusion of 7 mg/kg aminophylline. Venous blood was collected at timed intervals over 15 minutes to construct ICG concentration-time graphs. Pharmacokinetic values were calculated using non-compartmental methods. Estimated hepatic blood flow decreased from 790 +/- 190 to 665 +/- 100 ml/minute (p less than 0.05) after administration of aminophylline.

Comparison of assay procedures used to measure total and unbound concentrations of quinidine.

Individualized quinidine dosing through the assessment of serum concentrations is warranted because of the wide variability observed in its pharmacokinetic behavior and its reported narrow therapeutic index. The free fraction of quinidine also varies widely. Thus the development of procedures that could be widely used to determine quinidine free concentrations would be highly desirable. It was the purpose of this study to evaluate several procedures available to determine total serum quinidine concentrations (rate nephelometry [ICS], homogenous enzyme immunoassay [EMIT], and high-performance liquid chromatography [HPLC]). Furthermore, in samples from 46 patients, equilibrium dialysis and ultrafiltration procedures were compared for their ability to estimate quinidine free fraction. Finally, unbound concentrations of quinidine were compared using a modified EMIT procedure and a standard HPLC method to quantitate quinidine in ultrafiltrates from patient samples. For the measurement of total quinidine concentrations, reasonable agreement was seen when EMIT and ICS systems were compared with HPLC (ICS = 1.03.HPLC + 0.96, r = 0.93; EMIT = 1.08.HPLC + 0.38, r = 0.93) The mean errors, however, for these procedures were high (ICS +70 percent, range +7 to +233 percent; EMIT +35 percent, range 0 to 110 percent). Quinidine free fractions (QFF) determined by equilibrium dialysis (E) and ultrafiltration (U) showed good agreement (QFF(U) = 1.11.QFF(E) +0.0; r = 0.96). Unbound quinidine concentration determined by EMIT analysis of ultrafiltrate substantially overestimated the values obtained by HPLC analysis (mean error by EMIT 104 +/- 59 percent). It is concluded that HPLC is the method of choice for determining both total and unbound serum quinidine concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics and pharmacodynamics of quinidine and 3-hydroxyquinidine.

1. The pharmacokinetics and pharmacodynamics of quinidine and 3-hydroxyquinidine based upon measurements of total and unbound serum concentrations were determined after a single dose (400 mg) and at steady state (200 mg every 6 h). 2. The oral clearance (7.6 +/- 1.9 vs 4.8 +/- 2.0 ml min-1 kg-1; P less than 0.05) and renal clearance (1.2 +/- 0.3 vs 0.63 +/- 0.25 ml min-1 kg-1; P less than 0.005) or quinidine were lower during steady state than after the single dose. 3. The area under the serum concentration vs time curve (AUC) of 3-hydroxyquinidine was greater at steady state than after the single dose (2.0 +/- 0.7 vs 3.0 +/- 0.6 mg l-1 h; P less than 0.05) and its renal clearance was less (3.0 +/- 1.1 vs 1.54 +/- 0.38 ml min-1 kg-1; P less than 0.05). 4. The slope of the relationship between quinidine concentration and change in QTc interval was greater at steady state (40.1 +/- 21.7 vs 72.2 +/- 41.7 ms/(mg l-1); P less than 0.05).

Total and unbound concentrations of quinidine and 3-hydroxyquinidine at steady state.

Recent reports indicate that the metabolite of quinidine, 3-hydroxyquinidine, is pharmacologically active. It was the primary purpose of this study to determine total and unbound concentrations of quinidine and 3-hydroxyquinidine in 25 patients receiving quinidine for therapeutic purposes. At the peak, total quinidine and 3-hydroxyquinidine concentrations were 2.7 +/- 1.2 micrograms/ml and 0.57 +/- 0.33 micrograms/ml, respectively, and at the trough they averaged 2.0 +/- 0.91 micrograms/ml and 0.44 +/- 0.25 micrograms/ml. Interestingly, the unbound 3-hydroxyquinidine concentration frequently exceeded the unbound quinidine concentration, averaging 0.30 +/- 0.28 micrograms/ml at the peak and 0.22 +/- 0.14 micrograms/ml at the trough. Quinidine concentrations averaged 0.24 +/- 0.15 micrograms/ml and 0.18 +/- 0.12 micrograms/ml. The ratio of unbound 3-hydroxyquinidine: quinidine was significantly influenced by the unbound clearance of quinidine (r = 0.66). At low clearance values concentrations of both substances were elevated, with the quinidine concentration consistently exceeding that of 3-hydroxyquinidine. In contrast, at high clearance values 3-hydroxyquinidine concentrations were elevated and consistently exceeded the quinidine concentration. Thus, when quinidine concentrations are used to monitor the pharmacodynamic effect of quinidine, it is most appropriate to evaluate unbound concentrations of both quinidine and 3-hydroxyquinidine.