Pharmacokinetics of Thiopental Enantiomers during and following Prolonged High-dose Therapy

Background Thiopental is used as a racemate; however, this is not generally recognized. During conditions of prolonged high-dose therapy, the pharmacokinetics of thiopental may become nonlinear, but whether this derives from one or both enantiomers has not been evaluated. The authors determined the pharmacokinetics of R- and S-thiopental and serum concentrations of R- and S-pentobarbital from prolonged high-dose infusion of thiopental for neuroprotection. Methods Twenty patients received a mean thiopental dose of 41.2 g over a mean duration of 95 h. R- and S-thiopental enantiomer serum concentration-time data from 18 patients were fitted with two models: a linear one-compartment model with first-order output, and a nonlinear one-compartment model with Michaelis-Menten output. Results Nonlinear models were preferred in 16 of 18 patients. Paired analysis indicated that steady state clearance (Clss) and volume of distribution (Vd) were higher for R-thiopental (0.108 vs. 0.096 l/min, P < 0.0001; and 313 vs. 273 l, P < 0.0005, respectively); maximal rate of metabolism (Vm) was higher for S- than for R-thiopental (1.01 vs. 0.86 mg x l(-1) x h(-1), P = 0.02); elimination half-lives did not differ (14.6 vs. 14.7 h, P = 0.8); unbound fractions (f(u)) of R- and S-thiopental were 0.20 and 0.18, respectively, P < 0.0001). The differences in mean Clss, Vd and Vm were not significant when adjusted by f(u). Plasma concentrations of R- and S-pentobarbital were relatively small and unlikely to be of clinical significance. Conclusion The pharmacokinetics of R- and S-thiopental became nonlinear at these doses. The pharmacokinetic differences between R- and S-thiopental, although small, were statistically significant and were influenced by the higher f(u) of R-thiopental.

Download Full-text

Pharmacokinetic Evaluation of anti-HIV Drug Interactions: Effect of Zidovudine on 2′-3′-Dideoxyinosine Kinetics in Monkeys

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029300400304 ◽

1993 ◽

Vol 4 (3) ◽

pp. 155-159 ◽

Cited By ~ 2

Author(s):

M. Qian ◽

A. R. Swagler ◽

M. Mehta ◽

C.T. Vishwanathan ◽

J. M. Gallo

Keyword(s):

Dose Group ◽

Plasma Concentrations ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

High Dose ◽

Combination Regimen ◽

Time Profiles ◽

Elimination Half ◽

Constant Rate ◽

Rate Infusion

The current investigation was conducted to determine if zidovudine (AZT) altered the pharmacokinetics of dideoxyinosine (ddl) in non-hurnan primates, an appropriate animal model for AZT and ddl pharmacokinetics in human. Each of nine animals received 20 mg kg−1 of ddl intravenously in the absence and presence of two different dosage regimens of AZT. For each combination regimen, AZT was administered as a combined i.v. bolus-constant rate infusion regimen for 30 min that produced AZT plasma concentrations of about 4 μg ml−1 in six animals (low dose group) and 11 μg ml−1 in three others (high dose group). Serial blood samples were collected, and pharmacokinetic parameters for ddl were calculated based on plasma ddl concentrations measured by HPLC techniques. The pharmacokinetics of ddl given alone in the first phase of the low ( n = 6) and high ( n = 6) dose AZT groups, resulted in a mean elimination half-life 1.54 and 1.9h, a mean total clearance of 0.62 and 0.731 h−1 kg−1, and a mean steady state volume of distribution of 1.02 and 0.891 kg−1, respectively. Following combined ddl and AZT administrations, in both the low and high dose AZT groups, plasma concentration-time profiles of ddl were similar for each monkey, and no statistical differences were observed in the pharmacokinetic parameters compared to those obtained when ddl was given alone. The fact that AZT does not alter the pharmacokinetics of ddl at the range of AZT dose studied provides a basis for rational dosage design for combined ddl and AZT treatments in HIV infection.

Download Full-text

Phase I Clinical and Pharmacologic Trial of Intravenous Estramustine Phosphate

Journal of Clinical Oncology ◽

10.1200/jco.2002.20.4.1115 ◽

2002 ◽

Vol 20 (4) ◽

pp. 1115-1127 ◽

Cited By ~ 5

Author(s):

Gary Hudes ◽

Naomi Haas ◽

Gwen Yeslow ◽

Thomas Gillon ◽

Per Olov Gunnarsson ◽

...

Keyword(s):

Peak Plasma ◽

Plasma Concentrations ◽

Area Under The Curve ◽

Maximum Tolerated Dose ◽

Volume Of Distribution ◽

High Dose ◽

Weekly Dose ◽

Estramustine Phosphate ◽

Active Metabolites ◽

Elimination Half

PURPOSE: To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of intravenous estramustine phosphate (IV EMP). PATIENTS AND METHODS: A total of 31 patients with hormone-refractory prostate cancer received IV EMP as a 30- to 90-minute infusion weekly (n = 28) or for 3 consecutive days followed by a single weekly dose (n = 3). IV EMP dose was escalated from 500 to 3,000 mg/m2. Pharmacokinetics of EMP and the metabolites estramustine (EaM), estromustine (EoM), estradiol, and estrone were assessed after weeks 1 and 4 of treatment. RESULTS: The initial IV EMP infusion caused perineal discomfort that was ameliorated by lengthening the infusion time. Other common toxicities were grade 1 to 2 hepatotoxicity, nausea or vomiting, and fatigue or malaise. Lower-extremity thrombosis occurred in one patient, and two others developed upper-extremity thrombosis associated with venous infusion catheters. Dose-limiting fatigue and hypotension occurred at 3,000 mg/m2, and cumulative fatigue developed after multiple cycles at 2,500 mg/m2. Mean EMP clearance, estimated steady-state volume of distribution, and elimination half-life were 3.7 L/h, 10.6 L, and 3.7 hours, respectively. Variability of EMP clearance was 21%, and variation in area under the curve per dose for the metabolites was 28% to 36%. Elimination half-lives of EoM and EaM were 110 hours and 64 hours, and peak plasma concentrations of these active metabolites exceeded 10 μmol/L after IV EMP doses ≥ 2,000 mg/m2. CONCLUSION: High-dose IV EMP can be administered safely as a weekly short infusion to patients with HRPC. High peak concentrations of active metabolites after IV EMP may provide an advantage over oral EMP in antimicrotubule drug combinations.

Download Full-text