Pharmacokinetics intravenous infusion

Latimer WM (1952) Oxidation potentials. Prentice-Hall, Englewood Cliffs Lee P, Mohammed N, Marshall L, Abeysinghe RD, Hider RC, Porter JB, Singh S (1993) Intravenous infusion pharmacokinetics of desferrioxamine in thalassemic patients. Drug Metab Dispos 21 640-644... 

Little is known regarding the pharmacokinetic properties of volatile nitrites in humans, particularly isobutyl nitrite and its primary metabolite, isobutyl alcohol. In rodents, after an intravenous infusion of isobutyl nitrite, blood concentrations peaked rapidly and then declined, with a half-life of 1.4 minutes and blood clearance rate of 2.9 L/min/kg (Kielbasa and Fung 2000). Approximately 98% of isobutyl nitrite is metabolized rapidly to isobutyl alcohol, concentrations of which also decline rapidly, with a half-life of 5.3 minutes. Bioavailability of inhaled isobutyl nitrite at a concentration of 300-900 ppm is estimated to be 43%. 

Sculier, J. P., Coune, A., Brassine, C., Laduron, C., Atassi, G., Ruysschaert, J. M., and Fruhling, H. (1986). Intravenous infusion of high doses of liposomes containing NSC 251635, a water-insoluble cytostatic agent. A pilot study with pharmacokinetic data, J. Clin. Oncol., 4, 789-797. 

Topotecan inhibits topoisomerase I to cause single-strand breaks in DNA. The pharmacokinetics of topotecan can be described by a two-compartment model, with a terminal half-life of 80 to 180 minutes, with renal clearance accounting for approximately 70% of the clearance.19 Topotecan has shown clinical activity in the treatment of ovarian and lung cancer, myelodysplastic syndromes, and acute myelogenous leukemia. The intravenous infusion may be daily for 5 days or once weekly. Side effects include myelosuppression, mucositis, and diarrhea. 

Dopamine, a vasodilator, has been widely used for treatment of acute circulatory failure. However, since dopamine is rapidly metabolized when administered orally, its use has been limited to intravenous infusion. Murata et al., studied the bioavailability and the pharmacokinetics of orally administered dopamine (DA). The oral administration of DA to dogs resulted in an absolute bioavailability of approximately 3%. To minimize the extensive first-pass metabolism of DA, a dopamine prodrug, V-(/V-acetyl-l-mcLhionyl)-o,o-bis(cLhoxycarbonyl)dopamine (TA-870), was synthesized [28] (Fig. 6). Since DA is a substrate for both mono-... 

Mallo, C., Zaidan, R., Galy, G. et al. (1990). Pharmacokinetics of melatonin in man after intravenous infusion and bolus injection. Fur. ]. Clin. Pharmacol. 38, 297-301. 

Kurata T, Shimada Y, Tamura T, Yamamoto N, Hyodo 1, Saeki T, Takashima S, Fujiwara K, Wakasugi H, Kashimura M. (2000) Phase 1 and pharmacokinetic study of a new taxoid, RPR 109881A, given as a 1-hour intravenous infusion in patients with advanced solid tumors. J Clin Oncol 18 3164-3171. 

Rossignol DP, Wasan KM, Choo E, Yau E, Wong N, Rose 1, Moran 1, Lynn M. (2004) Safety, pharmacokinetics, pharmacodynamics and plasma lipoprotein distribution of eritoran (E5564) during continuous intravenous infusion into healthy volunteers. Antimicrob Agents Chemother 48 3233-3240. 

There is substantial variability in the pharmacokinetics of vinblastine in patients. Evidence has been obtained that implicates altered liver function and dose-dependent elimination as contributing factors to the variable pharmacokinetics. When vinblastine was administered by a bolus injection, a mean terminal elimination half-life of 29.2 hr was estimated for a group of 24 patients, but the half-lives ranged from a low value of 16 hr to a high value of 65 hr (55). When vinblastine was administered by intravenous infusion, clearance of the drug appeared to decrease with time over a 4-month period decreases in serum albumin values were found to be correlated with decreases in the clearance of vinblastine. 

Pharmacokinetics The pharmacokinetic profile of alemtuzumab was studied in a rising-dose trial in non-Hodgkin s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Campath was administered once weekly for a maximum of 12 weeks. Following intravenous infusions over a range of doses, the maximum serum concentration (C ax) and the area under the curve (AUC) showed relative dose pro-... 

Pharmacokinetics. The aminoglycosides are not reliably absorbed following oral dosing, so they are administered primarily by intravenous infusion or intramuscular injection. Distribution throughout the vascular and interstitial space is fairly rapid, but intracellular, cerebrospinal fluid, and bronchial secretion levels are generally low. Most of the administered dose is eliminated unmetabolized in the urine. 

Lotsch, J., A. Stockmann, G. Kobal, K. Brune, et al., Pharmacokinetics of morphine and its glucu-ronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers, Clin. Pharmacol. Ther., 60(3), 316-325, 1996. 

A. Roskey, and S. Agrawal. 1998. Pharmacokinetics and metabolism of an oligodeoxynucleotide phosphorothioate (GEM91) in cynomolgus monkeys following intravenous infusion. Antisense Nucleic Acid Drug Dev. 8 43—52. 

Supko, J.G..T.J. Lynch, J.W. Clark, R. Fram, L.F. Allen, R. Velagapudi, D.W. Kufe, and J.P. Eder, Jr. 2000. A phase I clinical and pharmacokinetic study of the dolastatin analogue cemadotin administered as a 5-day continuous intravenous infusion. Cancer Chemother. Pharmacd. 46 ... 

The pharmacokinetic properties of conivaptan HCl (1) in rats and dogs have not been reported in the literature. In humans, peak plasma concentrations of 1 occurred 0.67-2 h after oral administration to healthy males, with conivaptan HCl (1) showing 34-55% oral bioavailability.27 Intravenous infusion of 1 revealed a mean terminal elimination half-life of 5 h and mean clearance of 15.2 L/h,28 along with a volume of distribution of 34 L.27 At plasma concentrations of 10-1000 ng/mL, conivaptan is > 99% bound to human plasma proteins.28... 

Pharmacokinetics Slow intravenous infusion is employed for treatment of systemic infections or for prophylaxis. Because vancomycin is not absorbed after oral administration, this route is only employed for the treatment of antibiotic-induced colitis due to Q difficile. Inflammation allows penetration into the meninges. Metabolism is minimal 90-100 % is excreted by glomerular filtration. [Note Dosage must be adjusted in renal failure since the drug will accumulate. Normal half-life is 6-10 hours compared to over 200 hours in end-stage renal disease.]... 

Fong KL, Crysler CS, Mico BA, Boyle KE, Kopia GA, Kopaciewicz L, Lynn RE. Dose-dependent pharmacokinetics of recombinant tissue-type plasminogen activator in anesthetized dogs following intravenous infusion. Drug Metab Dis 1988 16 201-6. 

To illustrate the type of data that can be obtained using the study discussed, a high level summary of the pharmacokinetic results obtained from the study described above under Procedure is presented below. Due to the anticipated mode of action of the drug (blood pressure lowering) in this example, instead of an intravenous bolus injection an intravenous infusion over 30 minutes was chosen. 

The pharmacokinetics and absolute oral systemic availability of zaleplon have been assessed in a partially randomized, single-dose, crossover study in 23 healthy subjects, who received intravenous infusions of zaleplon 1 and 2.5 mg during the first and second periods and were then randomly assigned to receive an oral dose of 5 mg or an intravenous infusion of 5 mg in a crossover design (7). The oral and intravenous doses of zaleplon were well tolerated. Somnolence, abnormal vision, diplopia, and dizziness were the most commonly reported adverse events. 

Pique JM, Feu F, de Prada G, et al. (2002) Pharmacokinetics of omeprazole given by continuous intravenous infusion to patients with varying degrees of hepatic dysfunction. Clin Pharmacokinet 41 999-1004. 

Reaction rate parameters required for the distributed pharmacokinetic model generally come from independent experimental data. One source is the analysis of rates of metabolism of cells grown in culture. However, the parameters from this source are potentially subject to considerable artifact, since cofactors and cellular interactions may be absent in vitro that are present in vivo. Published enzyme activities are a second source, but these are even more subject to artifact. A third source is previous compartmental analysis of a tissue dosed uniformly by intravenous infusion. If a compartment in such a study can be closely identified with the organ or tissue later considered in distributed pharmacokinetic analysis, then its compartmental clearance constant can often be used to derive the required metabolic rate constant. 

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