The effects of non-steroidal anti-inflammatory drugs on the disposition of methotrexate in patients with rheumatoid arthritis.

We have studied the pharmacokinetics of methotrexate in patients with rheumatoid arthritis concurrently taking the most commonly used non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, diclofenac, naproxen, indomethacin, and ibuprofen. The area under the curve, the total systemic clearance, the distribution volume, and the half-life of methotrexate in patients receiving concurrent NSAID therapy did not change significantly (at p < 0.05). Concurrent treatment with NSAIDs resulted in increased inter-patient variability of methotrexate concentration, possibly as a result of biochemical interactions; however, it does not appear clinically relevant. The data suggest that the NSAIDs do not significantly affect the disposition of methotrexate, contrary to some of the earlier reports.

Partial-area method in bioequivalence assessment: naproxen.

Regulatory authorities require demonstration of bioequivalence through comparisons of different pharmacokinetic parameters, the area under the plasma concentration-time curve (AUC), the maximum plasma concentration (Cmax), and the time to reach peak concentration (Tmax). The applicability and validity of regulatory requirements have been widely criticized on statistical and clinical relevance grounds. For most noncomplicated absorption models, the AUC correlates well with the extent of absorption. However, in nonlinear models of absorption, in mechanisms involving recycling of drugs, and for drugs with long half-life, the use of total AUC (from zero to infinity) can give erroneous and clinically irrelevant results since the area is mostly determined by elimination phase or by recycling. The calculation of total AUC also involves prolonged sampling, adding to the cost and risks associated with bioequivalence studies. The use of Cmax or Tmax as a measure of rate of absorption, to correlate with clinical relevance, is widely criticized on logical, technical, and statistical grounds. For drugs used on a multiple-dose basis, Cmax and Tmax evaluations become redundant since the average plateau concentration is not affected by these parameters. To resolve the drawbacks in the traditional methodology of bioequivalence evaluation, the use of partial areas in lieu of total AUC, Tmax, and Cmax is suggested. This study investigates the logic and robustness of the partial-area method in establishing bioequivalence. We conclude that the 5h AUC is a more relevant parameter to establish naproxen bioequivalence than AUCinf. We recommend against using symmetrical confidence intervals and report excellent agreement among several methods of calculating confidence intervals, probability values, and nonparametric tests. We suggest that a single-point short-term AUC is a better indicator of the bioequivalence of generic products than the total AUC, Cmax, and Tmax as required currently by the regulatory authorities.

Dose dependent pharmacokinetics of naproxen in man.

The pharmacokinetics of one of the most widely used non-steroidal antiinflammatory drugs, naproxen, were studied in 28 healthy human volunteers at the two most commonly used dose levels, viz., 250 mg and 500 mg, in a cross-over design. The plasma levels of naproxen were analysed by a modified high-pressure liquid chromatography method. The plasma concentrations at higher doses were not proportional to dose, indicating a non-linearity in the pharmacokinetics at the dose levels studied; this finding is new since earlier studies had studied only higher doses and assumed that at lower doses the pharmacokinetics would be linear. There was, however, no significant difference in the elimination half-life (rate constant), time to reach peak concentration (Cmax), mean residence time (MRT), or area under first moment curve (AUMC). The clearance and distribution volume of naproxen were substantially increased at higher dose resulting in statistically lower proportional concentration and the total area under the curve (AUC). These observations are explained on the basis of a change in the plasma protein binding resulting in more free naproxen available for quicker clearance and wider penetration into tissues. These findings have several important clinical implications for the long-term use of naproxen as an antiarthritic drug. It is proposed that the clinical efficacy of naproxen can be increased and side-effects reduced by giving it in small divided doses instead of large doses.

The effect of caffeine on the pharmacokinetics of acetaminophen in man.

The influence of caffeine (60 mg) was studied on the pharmacokinetic characteristics of acetaminophen (500 mg single dose) in ten healthy male human volunteers in a complete cross-over design. A high-performance liquid chromatography (HPLC) method was used to analyse serum drug concentrations. Caffeine caused a highly significant (p < 0.01) increase in AUC and AUMC, a significant (p < 0.05) increase in Cmax, and a significant (p < 0.05) decrease in clearance (C1/F) of acetaminophen. We conclude that caffeine taken in doses commonly available commercially or in a cup of coffee can significantly potentiate the therapeutic potential of acetaminophen in man.

Pharmacokinetics of aditoprim and trimethoprim in buffalo calves.

Pharmacokinetic parameters of two antifolates, trimethoprim and aditoprim, were studied in buffalo calves. The elimination half-life of aditoprim (6.14 h) was nearly twice as long as that of trimethoprim (3.08 h) and compares well with values observed in heifers. This longer half-life of aditoprim is a result of its much larger distribution volume (four to five times larger) because the clearance of aditoprim was about twice as high as that of trimethoprim. The longer half-life of aditoprim is expected to give a longer duration of in vivo bacteriostatic activity than that of trimethoprim.

Disposition kinetics of 7,12-dimethylbenz(a)anthracene in rats.

One of the most potent carcinogens is 7,12-dimethylbenz(a)anthracene (7,12-DMBA), which is used routinely to conduct studies to evaluate carcinogen inhibitors. Its pharmacokinetics have not been reported in the literature. In view of its significant effects on drug metabolizing enzymes and clearance mechanisms, it is important to know its disposition characteristics. In this study, we monitored the disposition characteristics of 7,12-DMBA in rats as a function of dose range commonly used in carcinogenesis studies. A mean residence time of 40-55 min was observed; the total body clearance ranged from 8-13 l kg-1. No effect of dose was observed on the pharmacokinetic parameters. This suggests that the dose-dependent effects of 7,12-DMBA carcinogenesis are related to its transient disposition characteristics.

Effect of dehydration on the disposition kinetics of erythromycin in rabbits.

The effect of water deprivation on the physiologic, biochemical, and disposition parameters of erythromycin was investigated in rabbits. The packed cell volume, plasma glucose, and total lipid concentration increased significantly in dehydration. The pharmacokinetic parameters of erythromycin after intravenous administration also changed, suggesting a need for monitoring toxicity of erythromycin in the water-deprived population.

Chloramphenicol clearance in typhoid fever: implications for therapy.

We prospectively studied the pharmacokinetics of intravenous Chloramphenicol succinate (CS) in children (age 6 months-14 years) with culture proven typhoid fever (n = 30) and non typhoidal illnesses (n = 10). CS was administered in three different dosage regimens (50, 75 and 100 mg/kg/d-q 6 hourly). Liver function tests were monitored. Plasma trough and peak chloramphenicol concentrations were measured by HPLC analysis after 42 hrs. The 50 mg/kg/day dosage schedule was terminated midway through the study, as blood levels were consistently low and two patients with typhoid relapsed, children with typhoid had significantly lower clearance of CS in comparison with those with non-typhoidal illness (0.29 +/- 0.1 versus 0.5 +/- 0.37 1/kg/hr, P 0.05). There was no significant difference between mean peak and trough concentrations of chloramphenicol on 100 mg/kg/day and 75 mg/kg/day in children with typhoid. However, two children on 100 mg/kg/day dosage developed trough concentrations greater than 20 mcg/ml. No correlation was found between CS clearance and serum bilirubin, SGPT (alanine transaminase) and alkaline phosphatase. Our data show altered clearance of CS in children with typhoid and suggests that 75 mg/kg/day may be a safer dose in children with hepatic dysfunction in typhoid.

Pharmacokinetics of aditoprim in goats using a radioassay.

A simple, highly sensitive radioassay was developed for the activity of a newly discovered inhibitor of dihydrofolate reductase (DHFR), aditoprim. The procedure is based on the inhibition of binding of [3H]-methotrexate ([3H]MTX) with bacterial dihydrofolate reductase by the antifolate, aditoprim. The analytic sensitivity using this binding inhibition method was less than 5 ng in plasma. The procedure developed requires no extraction of the drug from the plasma. The variation of simultaneous duplicate determinations was 6.3 per cent, whereas the variability of plasma samples assayed on different days was less than 11 per cent. The assay developed was applied to study the pharmacokinetics of aditoprim in the goat. In comparison with trimethoprim (TMP), the new inhibitor of DHFR, aditoprim, had a longer half-life and a larger volume of distribution, suggesting enhanced and prolonged antibacterial activity of aditoprim over TMP.