John G. Kelly

Clinical pharmacokinetics of calcium antagonists. An update.

SummaryThe calcium antagonists are valuable and widely used agents in the management of essential hypertension and angina. There is an increasing number of new agents to add to the 3 prototype substances nifedipine, diltiazem and verapamil. These new agents are dihydropyridines structurally related to nifedipine. However, they tend to have longer elimination half-lives (t½β) and may be suitable for twice-daily administration. Amlodipine is an exception with a t½β in excess of 30h. Apart from elimination rates, however, the pharmacokinetic characteristics of the newer agents have a notable tendency to resemble those of the established agents. They are highly cleared drugs, are relatively highly protein bound. As they are subject to significant first-pass metabolism, old age and hepatic impairment will increase their plasma concentrations due to a reduced first-pass effect. Renal impairment does little to their pharmacokinetics since the fraction eliminated unchanged by the kidney is small. For most agents, plasma concentration-response relationships have been described. Interesting areas for further research include chronopharmacokinetics, stereoselective pharmacokinetics and lipid solubility. Drugs affecting hepatic blood flow and drug metabolising capacity have predictable interaction potential. Some of the newer calcium antagonists will, like verapamil, increase plasma digoxin concentrations. Verapamil and diltiazem decrease phenazone (antipyrine) metabolism and therefore tend to decrease the metabolism of other drugs.

Clinical pharmacokinetics of oral anticoagulants.

SummaryWarfarin is clinically the most widely used oral anticoagulant and its properties have been extensively studied. Assay methods for these compounds have until recently been relatively nonspecific. The advent of chromatographically based techniques has enabled a re-evaluation of the pharmacokinetics of oral anticoagulants, but most work continues to involve warfarin. The most important recent work has concerned the different anticoagulant potencies and metabolic pathways of the optical isomers of some of these drugs.The effects of age and some diseases on pharmacokinetics of warfarin have been examined but much remains to be done, especially with oral anticoagulants other than warfarin.There are several well established pharmacokinetic drug interactions with warfarin. There is a wide awareness of the drugs most likely to reduce anticoagulant effects by enzyme induction and alternative drugs can be used. Mechanisms of some interactions have been re-investigated. In vivo drug displacement interactions are complicated by the correlation between hepatic clearance of these drugs and the size of the unbound fraction in plasma. The interactions between phenylbutazone and warfarin and metronidazole and warfarin, resulting in potentiation of anticoagulant effect have been suggested to be due mainly to an inhibition of the metabolism of the more potent S isomer of warfarin.

Age and beta adrenoceptor–mediated function

Beta adrenoceptor–mediated responsiveness to isoproterenol was compared in young and old subjects using the production of cyclic adenosine monophosphate (cyclic AMP) by lymphocytes as an index. The mean log dose‐response curve for the elderly group was displaced to the right and the mean maximum response was less than that for the young subjects. The results corroborate evidence of a decreased response to isoproterenol‐induced increases in heart rate in the elderly and raise the possibility of a generalized decrease in beta adrenoceptor–mediated functions in old age.

A comparative study of a range of polymeric microspheres as potential carriers for the inhalation of proteins.

The aim of this study was to compare protein-loaded inhalable microparticles manufactured using a range of biocompatible polymers including hydroxypropyl cellulose (HPC), chitosan, hyaluronic acid, alginate, gelatin, ovalbumin and poly(lactide-co-glycolide) (PLGA). Spray-drying was used to prepare microparticles containing bovine serum albumin labeled with fluorescein isothiocyanate (BSA-FITC). Particles of respirable size and high protein loading were obtained. No evidence of BSA degradation was seen from PAGE analysis. The microparticles were mixed with mannitol as a carrier and powder aerosolization was assessed with a multi-dose dry powder inhaler (DPI) using a multi-stage cascade impactor. The mass median aerodynamic diameter (MMAD) ranged between 2.9 and 4.7 microm. Potential polymer toxicity in the lungs was compared by impinging the particles on Calu-3 monolayers and assessing the cytotoxicity, induction of cytokine release, changes in transepithelial permeability and electrical resistance. No toxic effects were observed with most of the polymers though some evidence of compromised cell monolayer integrity was seen for PLGA and ovalbumin. PLGA and gelatin microparticles caused a significant increase in IL-8 release. Of the polymers studied, PLGA showed the greatest toxicity. Certain polymers showed particular promise for specific protein delivery needs in the lungs, such as HPC to improve flow properties, sodium hyaluronate for controlled release, and chitosan and ovalbumin for systemic delivery.

Clinical pharmacokinetics of the newer ACE inhibitors. A review.

SummaryThe orally active angiotensin-converting inhibitors (ACE inhibitors) such as captopril and enalapril represent a significant therapeutic advance in the treatment of hypertension and congestive heart failure. Enalapril differs from captopril in several respects. It is a prodrug converted by hepatic esterolysis to the active (but more poorly absorbed) diacid, enalaprilat. Enalaprilat is more potent than captopril, more slowly eliminated and does not possess a sulfhydryl (SH) group.Enalapril was rapidly followed by a number of newer ACE inhibitors, the majority of which are similar to enalapril in that they are prodrugs, converted by hepatic esterolysis to a major active but poorly absorbed diacid metabolite. In one case (delapril) there are 2 active metabolites; in another (alacepril) the prodrug is converted in vivo to captopril. Lisinopril is an exception in that it is an enalaprilat-like diacid but with acceptable oral bioavailability, so that the prodrug route is not employed. The newer ACE inhibitors are at widely different stages of development, and it is not yet clear how many will reach regular clinical use. Of these newer drugs, lisinopril is the longest established and is the subject of the widest published literature. For a number there is as yet little published pharmacokinetic information.A variety of assay methods have been employed to characterise the pharmacokinetics of the ACE inhibitors, including enzymatic techniques, radioimmunoassay and chromatography. The peak plasma concentrations of the prodrugs are generally observed at around 1 hour and those of the diacid metabolites at about 2 to 4 hours. However, there is considerable variation within and between drugs, with benazepril and benazeprilat reaching peak concentrations early and enalapril and enalaprilat typical of later times to peak. Absorption of the active diacids is generally poor, and moderate (typically 30 to 70%) for the prodrugs. The bioavailability of lisinopril is about 25%.It is difficult to talk meaningfully about half-lives of the active drugs. The declines in their plasma concentrations are polyphasic and, if analytical sensitivity allows, active drug may be found at 48 hours or more following administration. This may reflect binding to ACE in plasma. Half-lives of accumulation are of the order of 12 hours; protein binding varies from little (lisinopril) to 90% (benazeprilat). Elimination is mostly renal but there may be biliary elimination for some, such as benazeprilat and fosinopril. The half-lives of the prodrugs are short.Impaired renal function decreases the elimination rate of the diacids. The largest effects on plasma concentrations are associated with severe renal impairment (glomerular filtration rate; < 30 ml/min). Increasing renal impairment is associated with longer times to peak of the diacids. Lisinopril and enalaprilat have been shown to be dialysable. Increasing age has variable effects, but is often accompanied by a decreased rate of elimination related to renal function, best demonstrated in population pharmacokinetic studies. Congestive heart failure may be associated with higher plasma concentrations but the pharmacokinetics of these agents in uncomplicated essential hypertension appear to be normal. The effects of hepatic impairment have been little studied, but severe hepatic impairment would be expected to result in impaired esterolysis of the prodrugs.

Digoxin “receptors” in neonates: An explanation of less sensitivity to digoxin than in adults

To investigate the possibility of altered digoxin receptor binding properties in neonates, we compared digoxin binding with erythrocytes from neonates and adults. Neonatal erythrocytes had two and a half times as many digoxin binding sites as adult erythrocytes. The neonatal “receptors” also had dissociation constants for digoxin that were twice the adult value. These findings suggest that differences in binding properties may explain the clinical observation of decreased sensitivity to digoxin in neonates and infants.

Investigation of the interaction of biodegradable micro- and nanoparticulate drug delivery systems with platelets

Objectives  Biodegradable micro‐ and nanoparticles are being increasingly investigated for drug delivery and targeting of therapeutics. The size and surface properties of these particles are important factors influencing their interaction and uptake by various cells, tissues and organs. Optimising these properties, to enhance cellular uptake, may increase their potential for interaction with other physiological components such as platelets resulting in platelet activation and inappropriate thrombus formation. The aim of this study was to investigate the potential interaction of particulates with platelets.

Nitrates in the Elderly

SummaryAlthough a significant proportion of patients receiving nitrates are elderly, surprisingly little published work is available describing the pharmacokinetics and pharmacodynamics of these agents in elderly patients. The lack of pharmacokinetic data is related to the difficulty in assaying nitrates and there are at present no definitive data describing the effect of aging on their bioavailability or elimination.A common finding in old age is of decreased hepatic first-pass metabolism. This would affect isosorbide-2-mononitrate and isosorbide-5-mononitrate less than isosorbide dinitrate and nitroglycerin (glyceryl trinitrate). Venous responsiveness to nitrates does not appear to alter with age, so that pharmacodynamic properties would not be expected to alter. However, decreased baroreflex function causes an increased tendency for posturally related side effects to occur. Mechanisms of tolerance are likely to be unaltered but any possible alteration in quantitative aspects of tolerance has not been studied.Nitrate therapy in the elderly would benefit from systematic investigation. At the moment, therapy needs to be titrated to the individual patient, with care taken to avoid age-related side effects by careful initiation of therapy and appropriate reviews of each patient.

Parallel synthesis and in vitro activity of novel anthranilic hydroxamate-based inhibitors of the prostaglandin H2 synthase peroxidase activity

Currently available non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin are directed at the cyclooxygenase (COX) site, but not the peroxidase (POX) activity of prostaglandin H2 synthase (PGHS). They are thus unable to inhibit the free-radical induced tissue injury associated with PGHS peroxidase activity, which can occur independently of the COX site. A lead compound, anthranilic hydroxamic acid (AHA) was found to have significant PGHS-POX inhibitory activity (IC50= 72 microM). To define the critical parameters for PGHS-POX inhibition, we investigated 29 AHA derivatives, synthesised from their acid precursors, using solid phase synthesis. In vitro analysis demonstrated a ten-fold improvement in inhibition with 3,5-diiodoanthranilic hydroxamic acid (IC50= 7 microM).

Fast disintegrating crystalline solid dispersions of simvastatin for incorporation into orodispersible tablets

Aim: Spray dried solid dispersion (SDP) of crystalline simvastatin (SIM) in a fast disintegrating matrix of superdisintegrants was studied as a method to enhance SIM dispersibility, rheology, compactibility and compressibility for incorporation into orodispersible tablets (ODTs). Materials and Methods: The superdisintegrants investigated were crospovidone (CP), sodium starch glycollate (SSG) and calcium silicate (CS) were spray dried with simvastatin to form SDPs. Results: The SDPs were characterized and the median particle size of SDPs was similar or greater than the SIM, contributing to good rheology of SDPs, while the low bulk density of SDPs indicated a high compactibility. Interestingly electron micrographs for SDPs showed a CP or CS carrier coating of the SIM crystals, contributing to its rheology. Thermal analysis and X-ray diffraction confirmed that SIM was crystalline in the SDPs and no interaction between SIM and any of the carrier(s) was shown by Fourier transform-infra red. Drug content analysis showed a SIM content of 90-95% in SDPs containing CP or CS, while a higher SIM content of 143% was found in SDP containing SSG. When formulated as ODTs, blend containing SIM SDPs in CP showed ease of tableting, regardless of the turret speed. In comparison, tablet blend consisting of a physical mix (PM) of SIM and CP could only be tableted at the lower turret speed of 7 rpm. ODTs formulated using SIM SDPs in CP showed a higher extent of dissolution, compared to the ODTs containing corresponding PM or the commercially available SIM Zocor® tablets (ANOVA, P < 0.05). Conclusion: SDP using disintegrants as carriers may offer an alternative formulation approach for ODTs of poorly soluble drugs.