Numerical Solution of Nonlinear Pharmacokinetic Equations: Effects of Plasma Protein Binding on Drug Distribution and Elimination

Coffey, John J.; Bullock, F. J.; Schoenemann, Paul T.

doi:10.1002/jps.2600601106

Cited by 58 publications

(10 citation statements)

References 13 publications

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“…total serum concentrations are decreased in uraemic rabbits, while free serum concentrations and tissue con centrations are not changed. This discrepancy between the results with phenylbutazone and phenytoin is in agreement with the theoretical consideration that alterations in drug distribu tion due to changes of binding in serum or tissues are most marked for drugs with a small volume of distribution (4,5).…”

Section: Discussionsupporting

confidence: 53%

Distribution of Antipyrine, Phenylbutazone and Phenytoin in Experimental Renal Failure

Ap¹,

Fm²,

Mt³

et al. 1981

Pharmacology

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Concentrations of antipyrine, phenylbutazone and phenytoin were measured in serum and in tissues of rabbits with acute renal failure after uranyl nitrate injection, in view of our earlier finding that the volume of distribution of phenytoin and of phenylbutazone is increased in those animals. Concentrations of antipyrine in serum and in tissues were not altered in the uraemic rabbit. For phenylbutazone, total serum concentrations were decreased in uraemic rabbits; concentrations in brain, liver and fat were increased, while concentrations in other tissues and unbound serum concentrations were not significantly changed. For phenytoin, total serum concentrations were decreased and unbound serum concentrations and tissue concentrations were not significantly changed in uraemic rabbits. Calculation of the ratios of tissue concentrations over unbound serum concentrations suggests that the increased distribution volume of phenylbutazone and phenytoin in the uraemic rabbit is due to the decreased serum binding rather than to changes in tissue binding.

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Section: Discussionsupporting

confidence: 53%

Distribution of Antipyrine, Phenylbutazone and Phenytoin in Experimental Renal Failure

Ap¹,

Fm²,

Mt³

et al. 1981

Pharmacology

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“…Ceftriaxone was given as an intravenous infusion over 15 minutes. Blood samples (2.5 mL) were collected before and at 7, 15, and 30 minutes and 1, 2, 3, 4,6,8,10,12,18, and 24 hours after the start of the infusion. Blood was centrifuged at room temperature, and the plasma was separated and frozen at −70°C until assayed.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of Ceftriaxone in Liver‐Transplant Recipients

Toth

Abdallah

Venkataramanan

et al. 1991

The Journal of Clinical Pharma

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The disposition of ceftriaxone was studied after a single 2 g intravenous dose in seven patients 3 to 5 days after liver transplantation. Ceftriaxone concentrations in plasma, urine, and bile were measured by HPLC, and plasma protein binding was determined by equilibrium dialysis. Plasma protein binding was nonlinear, and the unbound fraction varied between 0.05 and 0.56. Both capacity and affinity were markedly different from reported values for normal subjects. The pharmacokinetic parameters obtained were: total body clearance (TBC), 11.2 ± 7.8 mL/hr/kg total and 44.8 ± 29.1 mL/hr/kg unbound; volume of distribution (V area ), 224 ± 76 ml/kg total and 767 ± 432 ml/kg unbound; steady-state volume of distribution (V ss ), 212 ± 68 mL/kg total and 651 ± 368 mL/kg unbound; terminal disposition half-life (t 1/2 ), 21.6 ± 14.3 hour total and 16.3 ±11.1 hour unbound. TBC for both total and free drug was considerably lower than literature values for normal subjects. V area for total drug was greater than normal, whereas the corresponding value for free drug was smaller than normal. The plasma ceftriaxone concentrations at 12 and 24 hours were above the reported minimum inhibitory concentration (MIC). The fraction of the administered dose excreted in urine over 24 hours was 38 ± 29% and did not differ markedly from that reported for normal subjects. Less than 2% of the administered dose was excreted in 24-hour bile; however, biliary concentrations were always above MIC. Ceftriaxone can be administered once or twice daily at a dose of 2 g/day for prophylaxis in liver transplant recipients.Ceftriaxone is a third-generation, parenteral cephalosporin with broad-spectrum activity against gram-positive and gram-negative pathogens.1 At the University of Pittsburgh, cefotaxime, another third-generation cephalosporin, is currently used for prophylaxis before and for 5 days after orthotopic liver transplantation. Ceftriaxone offers certain advantages when compared with cefotaxime. First, ceftriaxone has a half-life of 6 to 10 hours,2 and therefore, can be given less frequently than cefotaxime, which has a half-life of 1 to 2 hours. 3 Second, since liver transplant recipients are prone to infection of the biliary region, an antibiotic that maintains an adequate oncentration in this area is desirable. As much as 40% of parent ceftriaxone is excreted into the biliary tract,4 whereas cefotaxime is eliminated solely through the kidneys as the parent compound and as the metabolites.3 Wider pathogenic spectrum is another advantage of ceftriaxone.1 , 5 Since a large fraction of the dose of ceftriaxone is excreted in the bile, the functional status of the liver is expected to influence the disposition of ceftriaxone. The objective of the present study was to elucidate ceftriaxone pharmacokinetics in orthotopic liver transplant patients, and subsequently determine an optimized dosing regimen in this patient population.

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“…In a displacement interaction altered distribution between these compartments may offset changes in the elimination rate constant. The net change in tissue drug concentration, however, will be relatively small since the ratio of the tissue distribution volume to the plasma volume is relatively large (Coffey, Bullock & Schoenemann, 1971). These results demonstrate the usefulness of salivary drug estimations in the detection of changes in plasma protein drug binding.…”

Section: Discussonmentioning

confidence: 99%