Gary R. Matzke

Validation of the five-drug "Pittsburgh cocktail" approach for assessment of selective regulation of drug-metabolizing enzymes.

To determine whether the probe drugs caffeine, chlorzoxazone, dapsone, debrisoquin (INN, debrisoquine), and mephenytoin can be simultaneously administered as a metabolic cocktail to estimate in vivo cytochrome P450 (CYP) and N‐acetyltransferase enzyme activities.

Drug administration in patients with renal insufficiency : Minimising renal and extrarenal toxicity

SummaryRenal insufficiency has been associated with an increased risk of adverse effects with many classes of medications. The risk of some, but not all, adverse effects has been linked to the patient’s degree of residual renal function. This may be the result of inappropriate individualisation of those agents that are primarily eliminated by the kidney, or an alteration in the pharmacodynamic response as a result of renal insufficiency.The pathophysiological mechanism responsible for alterations in drug disposition, especially metabolism and renal excretion, is the accumulation of uraemic toxins that may modulate cytochrome P450 enzyme activity and decrease glomerular filtration as well as tubular secretion. The general principles to enhance the safety of drug therapy in patients with renal insufficency include knowledge of the potential toxicities and interactions of the therapeutic agent, consideration of possible alternatives therapies and individualisation of drug therapy based on patient level of renal function.Although optimisation of the desired therapeutic outcomes are of paramount importance, additional pharmacotherapeutic issues for patients with reduced renal function are the prevention or minimisation of future acute or chronic nephrotoxic insults, as well as the severity and occurrence of adverse effects on other organ systems. Risk factors for the development of nephrotoxicity for selected high-risk therapies (e.g. aminoglycosides, nonsteroidal anti-inflammatory drugs, ACE inhibitors and radiographic contrast media) are quite similar and include pre-existing renal insufficiency, concomitant administration of other nephrotoxins, volume depletion and concomitant hepatic disease or congestive heart failure. Investigations of prophylactic approaches to enhance the safety of these agents in patients with renal insufficiency have yielded inconsistent outcomes. Hydration with saline prior to drug exposure has given the most consistent benefit, while sodium loading and use of pharmacological interventions [e.g. furosemide (frusemide) dopomine/dobutamine, calcium antagonists and mannitol] have resulted in limited success. The mechanisms responsible for altered dynamic responses of some agents (benzodiazepines, theophylline, digoxin and loop diuretics) in renally compromised patients include enhanced receptor sensitivity secondary to the accumulation of endogenous uraemic toxins and competition for secretion to the renal tubular site of action. Application of the pharmacotherapeutic principles discussed into clinical practice will hopefully enhance the safety of these agents and optimise patient outcomes.

Evaluation of the influence of diabetes mellitus on antipyrine metabolism and CYP1A2 and CYP2D6 activity

Study Objective. To evaluate the metabolism of antipyrine, a general metabolic probe, caffeine, a probe for cytochrome P450 (CYP) 1A2 and N‐acetyltransferase activity, and dextromethorphan, a specific probe for CYP2D6 activity in patients with type 1 or 2 diabetes mellitus.

Determinants of Ceftriaxone Clearance by Continuous Venovenous Hemofiltration and Hemodialysis

Study Objective. To guide individual ceftriaxone dosages in patients receiving continuous renal replacement therapy.

Nonrenal toxicities of acetaminophen, aspirin, and nonsteroidal anti-inflammatory agents

Approximately 2% of the United States population consumes an analgesic, antipyretic, or nonsteroidal antiinflammatory drug (NSAID) each day. Aspirin and acetaminophen have been available to the public without a prescription (over-the-counter) for decades, while most NSAIDs are still only available with a prescription from a physician. The recent trend of switching NSAIDs from prescription to over-the-counter status may be perceived by some as an indication of their inherent safety. However, all these agents have been associated with a unique but overlapping safety profile. In fact, significant adverse events (AEs) on multiple organ systems, including the kidney and gastrointestinal tract, have been reported with most of these agents. In this review, the incidence of the nonrenal AEs of aspirin, acetaminophen, and selected NSAIDs are tabulated. The strengths of the causative associations are highlighted, the relative risks for the gastrointestinal and cardiovascular AEs are discussed, and the relationship to patient risk factors and drug characteristics, such as dose and half-life, are reviewed. The selection of the optimal agent for an individual patient depends on the balance between the desired pharmacodynamic response, the patients pharmacotherapy history, and the degree of AE risk one is willing to accept. Therapy should be initiated in all settings with the lowest possible dosage since the incidence of the major AEs is dose related.

Comparison of iothalamate clearance methods for measuring GFR.

Study Objective. To evaluate the bias and precision of three methods of measuring glomerular filtration rate (GFR) relative to a standard method.

The Effect of Renal Insufficiency and Hemodialysis on the Pharmacokinetics of Nalmefene

The disposition of nalmefene, an opioid antagonist intended for the reversal of opioid‐induced respiratory depression, and its primary metabolite nalmefene glucuronide, were characterized in adult volunteers with normal renal function and in patients with end‐stage renal disease (ESRD). The effect of hemodialysis on the elimination of nalmefene and nalmefene glucuronide also was assessed. Participants with normal renal function received a single intravenous dose of 2 mg, and patients with ESRD received two separate doses of 1 mg nalmefene hydrochloride. Terminal elimination half‐life (t1/2) of both nalmefene and nalmefene glucuronide was prolonged in patients with ESRD compared with that in participants with normal renal function. The steady‐state volume of distribution (Vdss) of nalmefene was significantly higher and total body clearance lower in patients with ESRD than in participants with normal renal function. Hemodialysis clearance of nalmefene was approximately 3.3% of total body clearance. Although the hemodialysis clearance of nalmefene glucuronide was 179.3 ± 24.1 mL/min and its t1/2 was significantly reduced during dialysis to 5.2 ± 2.3 hours, a dramatic rebound of nalmefene glucuronide concentrations of 75.7% was observed 7.7 ± 5.4 hours after the end of hemodialysis. Thus, hemodialysis does not result in clinically significant alterations in the disposition of nalmefene or its primary metabolite, nalmefene glucuronide. These data suggest that there is no pharmacokinetic basis for modification of the initial dosage, but maintenance doses, if needed, should be administered less frequently due to the prolonged elimination of the active moiety, nalmefene.

Impaired 6-hydroxychlorzoxazone elimination in patients with kidney disease: Implication for cytochrome P450 2E1 pharmacogenetic studies.

The purposes of this study were (1) to describe the disposition of chlorzoxazone and 6‐hydroxychlorzoxazone in patients with kidney disease, (2) to develop a population pharmacokinetic model including covariates that may influence the pharmacokinetic variability of both compounds, and (3) to examine the effect of covariates on the chlorzoxazone metabolic ratio.

Effect of renal insufficiency on CYP activity.

Clinical Pharmacology & Therapeutics (1996) 59, 155–155; doi:10.1038/sj.clpt.1996.120

Rapid microtiter plate assay for determination of inulin in human plasma and dialysate.

A rapid, sensitive, and reproducible microtiter plate assay for the determination of inulin in human plasma, dialysate, and phosphate-buffered saline (PBS) was developed. Plasma or PBS samples (100 microl aliquots) were prepared by the addition of indole-3-acetic acid (150 microl) and HCl (3 ml) and then briefly vortex-mixed. Samples were then incubated in a 60 degrees C water bath for 20 min, cooled in a room temperature water bath for 40 min, then diluted with deionized, distilled water (DDW; 3 ml) and again vortex-mixed. Finally, an aliquot (200 microl) of each sample was transferred to a 96-well microtiter plate and read spectrophotometrically at 490 nm. Dialysate samples were processed in a similar manner, but required an initial enzymatic step in order to remove dextrose and minimize assay interference. Samples (100 microl aliquots) were prepared by the addition of glucose oxidase/catalase solution (100 microl), briefly vortex mixed, and then incubated in a 37 degrees C water bath for 60 min, samples were then reacted with indole-3-acetic acid as before. Calibration curves were linear over the concentration range of 0.5-4 mg/ml or 0.025-0.4 mg/ml for plasma or PBS and dialysate, respectively; correlation coefficients (r(2)) were >0.99. The intra- and inter-day coefficients of variation in plasma, PBS, and dialysate were <15%. This method is well suited for the rapid analysis of large numbers of samples and is currently being used for in vitro investigations of solute removal by hemodialysis.