Virginia A. Johnson

Single-dose pharmacokinetics of ibuprofen and acetaminophen in febrile children

The disposition of antipyretic drugs is central to the understanding of their action in children. Accordingly, the authors measured plasma levels of acetaminophen and ibuprofen in 153 febrile children for 6 hours after a single dose of either acetaminophen (12.5 mg/kg) or ibuprofen (5 or 10 mg/kg). Cmax occurred about 2 1/2 hours before maximum antipyresis, when plasma acetaminophen or ibuprofen was 25 to 50% less than Cmax. Most plasma level data fit a one‐compartment open model, and this suggests a pharmacodynamic basis for the observed lag between Cmax and maximum antipyretic response. Plasma levels (and AUC0→∞) of ibuprofen 10 mg/kg were less than expected for a two‐fold increase in dose. For acetaminophen, the tlog was less than ibuprofen, Ka was more than ibuprofen, and β was less than ibuprofen. The ibuprofen β was not dose dependent, but the Vd was dose and model dependent. In contrast, ibuprofen Clp was dose and model independent. Acetaminophen pharmacokinetics were similar to those previously reported. Initial temperature, race, gender, prior medications, or diagnosis did not confound the results for ibuprofen or acetaminophen. Accordingly, a pharmacodynamic basis is a more likely explanation for the initial temperature effects found previously for antipyretic drugs in children. Ibuprofen (5 and 10 mg/kg) AUC0→∞ was higher in the older (≥ 2.5 yrs) children and the Vd and Clp were lower in the older children, when discriminated by age or pharmacokinetic parameters. The observed dose dependency of AUC0→∞ and the effect of age on ibuprofen disposition must be considered if pharmacokinetic interpretations are used to develop the antipyretic dose of ibuprofen in children.

Flurbiprofen in Post‐Partum Women: Plasma and Breast Milk Disposition

The plasma and milk disposition of flurbiprofen (FB) was assessed in healthy women during the early post‐partum period after multiple doses of FB. The results confirmed that a pragmatic study design is an attainable requirement for definitive statements about the excretion of FB in transitional milk. Nine doses of FB (50 mg per dose) were administered during three days. Paired milk and plasma samples were obtained during this period of dosing as well as after the last dose. The plasma data were used to derive an equation, which was then used to simulate cumulative plasma profiles for multiple doses given at unequal time intervals. The observed data corresponded to the simulated cumulative profiles of FB in plasma. The plasma elimination half‐life of FB during early lactation was slightly prolonged (mean 4.8 hrs) as compared to reported values for normal adult men. The peak plasma concentrations of FB were comparable to those reported for healthy volunteers. In 10 of 12 women (3–5 days post‐partum) the FB concentration in breast milk was less than 0.050 μg/ml. In two women the milk concentrations of FB were 0.06, 0.07 and 0.07 μg/ml as found in only three samples. We conclude that, on the basis of dose found in milk, FB is safe for women breast feeding their infants in the early post‐partum period.

Microanalytical high-performance liquid chromatographic assay for cefpirome in human milk and urine

To permit the characterization of cefpirome disposition in lactating females, a previously published high-performance liquid chromatographic (HPLC) method for determining the drug in serum was adapted for use with milk and urine. This automated, microanalytical technique requires 50 microliters of biological matrix, which is subjected to an isopropanol extraction. Chromatography was accomplished using a microbore HPLC system, a reversed-phase C18 column and a mobile phase of 0.3% triethylamine in water (pH 5.1). Cefpirome and the internal standard (beta-hydroxypropyltheophylline) were monitored using UV detection at 240 nm and had retention times of 2.84 and 5.05 min, respectively. The method was linear up to 500 mg/l for both matrices and had a limit of detection of 0.6 mg/l. The interday variation (relative standard deviation) at concentrations of 5.0, 50.0 and 500.0 mg/l was consistently less than 5% in both urine and breast milk. The method was found to be free from interference by other commonly administered medications and readily adaptable for use in clinical investigations. The ease of sample preparation, small sample volume requirement, short chromatographic time, apparent lack of interferences, analytical sensitivity and high precision and accuracy make this method ideal for use in pharmacokinetic investigations involving the determination of cefpirome in human milk and urine.

Bovine factor Xa and bovine trypsin: A comparison with respect to inhibition by some amidines and guanidines☆

Abstract The enzymatic activity of activated bovine blood clotting factor X toward the synthetic substrate N α-benzoyl- l -arginine ethyl ester and the inhibitory effects of a series of low molecular weight synthetic aromatic amidine and guanidine compounds on that activity were studied using the steady-state kinetic method. The kinetic parameters, K m and κ cat , and the apparent dissociation constant K i ′ for each inhibitor, were determined for activated factor X hydrolysis of Bz-Arg-OEt at 37 °C, pH 7.8 in 0.1 n NaCl and 0.001 m CaCl 2 . The same constants were determined for bovine β-trypsin under identical conditions. Comparison of kinetic constants determined for both enzymes shows that activated factor X binds the substrate Bz-Arg-OEt less efficiently than β-trypsin by several orders of magnitude. However, binding of the inhibitors benzamidine, p -aminobenzamidine, pentamidine, M&B 4596, phenylguanidine, and p -guanidinobenzoic acid is similar for both enzymes. The results indicate that these two closely related serine proteases differ little in the structural arrangement and accessibility of the anionic “pocket” at which these inhibitors bind. The large differences observed with respect to substrate binding activity probably reflect substantial structural differences between the two enzymes at secondary sites adjacent to the primary anionic site.

Pharmacologic factors contributing to variance in the milk to plasma ratio for acetaminophen in the goat.

A single-point estimate of the milk to plasma (M/P) drug ratio presupposes an invariant ratio. This may lead to erroneous conclusions about the amount of drug excreted in breast milk. A variance of the M/P ratio with regard to time has been shown for acetaminophen under standardized biologic conditions in the lactating goat. This ratio is potentially confounded by such factors as route of administration, dose amount and duration of exposure to the drug. Each factor was evaluated by computer simulations of the M/P ratio and by derivation of a ratio from empirical data in the goat. Route of administration was found to influence both the pattern and magnitude of the M/P ratio after acetaminophen dosing in the goat. Similar, but less, effects were found for duration of dosing. Dose itself did not influence the ratio. A temporal basis exists for each confounding factor. We thus propose that the M/P ratio is fundamentally variant with time under a standard set of biologic conditions. The contributing variance of confounding factors must be assessed if drug in milk dosing of the infant is to be accurately evaluated by use of the M/P ratio.

Fundamental Kinetics of Drug Excretion in Breast Milk

We have emphasized the variance of the M/P ratio with time after dosing (1). This variance is kinetically determined. Accordingly, variance in the M/P ratio may be confounded by factors altering the kinetic profile of drug concentration in the fluid of reference i.e., blood or milk. These factors include dose, route and duration of administration. We have evaluated each of these for their contribution to the temporal variance of the M/P ratio (2). These pharmacological manipulations were performed by using the goat as an animal model and with acetaminophen (APAP) as the test drug. Acetaminophen was chosen because it has a short elimination half-life and can be administered by either the oral or intravenous route in the goat.

Comparison of TDx and HPLC Methods for Urinary Lorazepam Glucuronide

Clinical Pharmacology & Therapeutics (1996) 59, 215–215; doi: 10.1038/sj.clpt.1996.360

INCREASED PLASMA CLEARANCE OF LORAZEPAM IN CYSTIC FIBROSIS DOES NOT REFLECT INCREASED GLUCURONYLTRANSFERASE ACTIVITY. 434

INCREASED PLASMA CLEARANCE OF LORAZEPAM IN CYSTIC FIBROSIS DOES NOT REFLECT INCREASED GLUCURONYLTRANSFERASE ACTIVITY. 434