Dion R. Brocks

Clinical Pharmacokinetics of Ketoprofen and Its Enantiomers

SummaryKetoprofen, a potent nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid class, has been used clinically for over 15 years in Europe, and has recently been introduced in the United States. Although it possesses a chiral centre, with only the S-enantiomer possessing beneficial pharmacological activity, all ketoprofen preparations to date are marketed as the racemate. Ketoprofen exhibits little stereoselectivity in its pharmacokinetics. The enantiomers have similar plasma time-courses and do not seem to interact with one another. Hence, the data generated using nonstereospecific assays may be used to explain the pharmacokinetics of individual enantiomers.The absorption of ketoprofen is rapid and almost complete when given orally. Sustained release dosage forms are available, which may be beneficial due to the short terminal phase half-life of ketoprofen (1 to 3h). They may also decrease local gastrointestinal side effects. Although with these preparations the peak plasma drug concentration is reduced and time to peak is prolonged, the bioavailability is the same as that with regular release counterparts. Ketoprofen binds extensively to plasma albumin, apparently in a stereoselective manner. Substantial concentrations of the drug are attained in synovial fluid, the proposed site of action of NSAIDs. It is eliminated following extensive biotransformation to inactive glucuroconjugated metabolite. There is about 10% R to S inversion upon oral administration. Conjugates are excreted in urine, and virtually no drug is eliminated unchanged. The excretion of conjugates is closely tied to renal function; accumulation of conjugates occurs in the elderly, but not in young subjects or patients. Significant drug interactions have been demonstrated for probenecid, aspirin and methotrexate. There appears to be circadian variation, particularly in the absorption of ketoprofen. The relationship between concentration and anti-inflammatory effect has yet to be elucidated for this drug.

Impact of lipoproteins on the biological activity and disposition of hydrophobic drugs: implications for drug discovery

In contrast to many traditional pharmaceutical agents that exhibit a high degree of aqueous solubility, new drug candidates are frequently highly lipophilic compounds. The aqueous environment of the blood provides a thermodynamically unfavourable environment for the disposition of such hydrophobic drugs. However, this limitation can be overcome by association with circulating lipoproteins. Elucidation of the mechanisms that dictate drug–lipoprotein association and blood-to-tissue partitioning of lipoprotein encapsulated drugs might yield valuable insight into the factors governing the pharmacological activity and potential toxicity of these compounds. This Review discusses the impact of hydrophobic drug–lipoprotein interactions on pharmacokinetics, drug metabolism, tissue distribution and biological activity of various hydrophobic compounds, and outlines how best to use this information in drug discovery and development programmes.

A systematic review of drug absorption following bariatric surgery and its theoretical implications

Demand for bariatric surgery has risen exponentially and bariatric patients often have multiple indications for post‐operative pharmacotherapy. The purpose of this study was to systematically review the published literature examining the effect of bariatric surgery on drug absorption.

Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma

Simultaneous inhibition of the vascular epithelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway may improve treatment response in advanced renal cell carcinoma (RCC). Everolimus, an oral mTOR inhibitor, and sunitinib, an oral tyrosine kinase inhibitor targeting VEGF, are standard agents in the management of metastatic RCC.

Clinical pharmacokinetics of ketorolac tromethamine.

SummaryKetorolac is a new chiral nonsteroidal anti-inflammatory drug (NSAID) which is marketed for analgesia as the racemate. The drug is administered as the water soluble tromethamine salt and is available in tablets or as an intramuscular injection. The absorption of ketorolac is rapid, Cmax being attained between 20 to 60 min. Its oral bioavailability is estimated to range from 80 to 100%. The drug is extensively bound (>99%) to plasma proteins and has a volume of distribution (0.1 to 0.3 L/kg) comparable with those of other NSAIDs. Only small concentrations of ketorolac are detectable in umbilical vein blood after administration to women in labour. The elimination half-life is between 4 and 6h and is moderate in comparison with other NSAIDs. The area under the plasma concentration-time curve of ketorolac is proportional to the dose after intramuscular administration of therapeutic doses to young healthy volunteers.Ketorolac is extensively metabolised through glucuronidation and oxidation; little if any drug is eliminated unchanged. Most of the dose of ketorolac is recovered in the urine as conjugated drug. Although ketorolac is excreted into the breast milk, the amount of drug transferred comprises only a small fraction of the maternal exposure. Little stereoselectivity was present in the pharmacokinetics of ketorolac in a healthy volunteer receiving single intravenous or oral doses. The elderly exhibit reduced clearance of the drug. Renal insufficiency appears to cause an accumulation of ketorolac in plasma, although hepatic disease may not affect the pharmacokinetics.

Effect of Gastric Bypass Surgery on the Absorption and Bioavailability of Metformin

OBJECTIVE Use of gastric bypass surgery is common and increasing. Over 40% of patients in diabetes remission after gastric bypass surgery may redevelop diabetes within 5 years. Metformin, the first-line drug for diabetes, has low bioavailability and slow, incomplete gastrointestinal absorption. We hypothesized that gastric bypass would further reduce the absorption and bioavailability of metformin. RESEARCH DESIGN AND METHODS In a nonblinded, single-dose pharmacokinetic study, 16 nondiabetic post–gastric bypass patients and 16 sex- and BMI-matched control subjects (mean age 40 years and BMI 39.2 kg/m2) were administered two 500-mg metformin tablets. Plasma metformin levels were sampled at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 h. Metformin absorption, estimated by the area under the curve (AUC) of the plasma drug concentrations from time 0 to infinity (AUC0-∞), was the primary outcome, and metformin bioavailability, assessed by measuring 24-h urine metformin levels, was a secondary outcome. RESULTS Compared with control subjects, metformin AUC0–∞ was increased in gastric bypass subjects by 21% (13.7 vs. 11.4 μg/mL/h; mean difference 2.3 [95% CI −1.3 to 5.9]) and bioavailability was increased by 50% (41.8 vs. 27.8%; 14.0 [4.1–23.9]). Gastric bypass patients had significantly lower AUC glucose levels over 8 h compared with control subjects (35.8 vs. 41.7 μg/mL/h; 5.9 [3.1–8.8]), but this was likely a result of differences in baseline fasting glucose and not metformin absorption. CONCLUSIONS Metformin absorption and bioavailability seem to be higher after gastric bypass, and this may have implications on dosing and toxicity risk. Studies are needed to confirm these findings and delineate potential mechanisms.

Stereoselectivity in the Pharmacodynamics and Pharmacokinetics of the Chiral Antimalarial Drugs

Several of the antimalarial drugs are chiral and administered as the racemate. These drugs include chloroquine, hydroxychloroquine, quinacrine, primaquine, mefloquine, halofantrine, lumefantrine and tafenoquine. Quinine and quinidine are also stereoisomers, although they are given separately rather than in combination.From the perspective of antimalarial activity, most of these agents demonstrate little stereoselectivity in their effects in vitro. Mefloquine, on the other hand, displays in vitro stereoselectivity against some strains of P. falciparum, with a eudismic ratio of almost 2: 1 in favour of the (+)-enantiomer. Additionally, for some of these agents (e.g. halofantrine, primaquine, chloroquine), stereoselectivity has been noted in the ability of the enantiomers to cause certain adverse effects.In recent years, stereospecific analytical methods capable of measuring the individual enantiomers after the administration of racemic drugs have been reported for a number of chiral antimalarial drugs. These assays have revealed that almost all the studied antimalarial drugs display stereoselectivity in their pharmacokinetics, leading to enantioselectivity in their plasma concentrations. Whereas the oral absorption of these agents appears to be non-stereoselective, stereoselectivity is often seen in their volume of distribution and/or clearance. With regard to distribution, plasma protein binding of some chiral antimalarial drugs exhibits a significant degree of stereoselectivity, leading to stereoselective distribution to blood cells and other tissues. Because of their low hepatic extraction ratios, stereoselective plasma protein binding also contributes to the stereoselectivity in the metabolism of these drugs. Chiral metabolites are formed from some parent antimalarial drugs, although stereoselective aspects of the pharmacokinetics of the metabolites are not well understood.It is concluded that knowledge of the stereoselective aspects of these agents may be helpful in better understanding their mechanisms of action and possibly optimising their clinical safety and/or effectiveness.

Multiple peaking phenomena in pharmacokinetic disposition.

Abstractmultiple peaking in the blood fluid concentration-time curve is a phenomenon occasionally encountered in pharmacokinetics. When it occurs, it can create difficulties in the determination and interpretation of pharmacokinetic parameters. Multiple peaking can occur as a consequence of a number of different mechanisms. These include, in addition to others, factors related to the formulation, be it the drug chemical entity itself or other formulation-related factors such as the excipients incorporated into the product design. Another contributing factor that can work in concert with the formulation is the physiological makeup of the gastrointestinal tract itself. This includes the pH and components of bile such as bile salts and phospholipids, the secretion of which is regulated by hormonal and dietary factors. In some cases, biochemical differences in the regional areas of the gastrointestinal tract, such as regiospecificity in bile concentrations and/or transport proteins, could contribute to windows for absorption that result in multiple peaking of xenobiotics. One of the most common sources of multiple peaking is contributed by biliary secretion followed by intestinal reabsorption of a drug, a process for which the term ‘enterohepatic recycling’ has been coined. This cause of multiple peaking is associated with special consideration in the calculation and interpretation of the drug clearance and volume of distribution. In this review, each of these various causes of multiple peaking is discussed, with incorporation of relevant examples for illustrative purposes.

Disposition of Drugs in Block Copolymer Micelle Delivery Systems : From Discovery to Recovery

Since their discovery in the early 1980s, polymeric micelles have been the subject of several studies as delivery systems that can potentially improve the therapeutic performance and modify the toxicity profile of encapsulated drugs by changing their pharmacokinetic characteristics. The efforts in this area have led in recent years to the advancement of several polymeric micellar formulations to clinical trials, some of which have shown promise in changing the biodistribution of the incorporated drug after intravenous administration as a means of tumour-targeted drug delivery. Recently, the possible benefit of polymeric micellar delivery in enhancing the absorption and bioavailability of incorporated drugs from alternative routes of drug administration has attracted interest. This article provides an overview of the effect of polymeric micellar delivery on absorption, distribution, metabolism and excretion of incorporated therapeutic agents. It also aims to assess the current information on the performance of polymeric micellar delivery systems in modifying the pharmacokinetics/pharmacodynamics of the incorporated drugs in clinical trials, and to re-examine the important structural factors required for successful design of polymeric micellar delivery systems capable of inducing favourable changes in the pharmacokinetics of the encapsulated drug.

The metabolism of amiodarone by various CYP isoenzymes of human and rat, and the inhibitory influence of ketoconazole

PURPOSE To evaluate the metabolism of amiodarone (AM) to desethylamiodarone (DEA) by selected human and rat cytochrome P450, and the inhibitory effect of ketoconazole (KTZ). METHODS Some important CYP isoenzymes (rat CYP1A1, 1A2, 2C6, 2C11, 2D1, 2D2, and 3A1 and human CYP1A1, 1A2, 2D6 and 3A4) were spiked with various concentrations of AM to determine the relative kinetic parameters for formation of DEA in the presence and absence of various concentrations of KTZ. RESULTS The formation of DEA was observed when AM was exposed to each of the CYP tested, although the rates were varied. Human CYP1A1 followed by 3A4 had the highest intrinsic clearance (CLint) for DEA formation whereas in rat, CYP2D1 followed by CYP2C11 had the highest CLint. Human and rat CYP1A2 seemed to have the lowest CLint. At high concentrations of AM and KTZ, near those expected in vivo, significant inhibition of all isoforms except for rat CYP1A2 was observed. At lower concentration ranges of both drugs, the inhibitory constant was determined. At these levels, KTZ was found to potently inhibit human CYP1A1 and 3A4 and rat 2D2 and 1A1. CONCLUSION Human CYP1A1 and 3A4 and rat CYP2D1 and 2C11 were most efficient in converting AM to DEA. For DEA formation, the in vivo administration of KTZ could inhibit other CYP isoforms besides CYP3A in human and rat.