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Chirality in Clinical Pharmacology

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Chirality in Clinical Pharmacology t+,q'q3 Chirolity in Clinicol Phormqcology: Sludies with Keloprofen A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy by Peter John Hayball B.Pharm., B.Sc.(Hons), Department of Clinical and Experimental Pharmacology, University of Adelaide June, 1993. A"^nde.,l tqq 3 1l Conlents Abstract v Declnrøtion vi Acknowledgements vü Publications ín Support of thß Thesis vüi Abbreviations and Symbols ix Chopter I lntroduction: Enontioseleclive Clinicol Phormocology page I 1.1 Terminology page I 1.2 Stereoisomerism: A Historical Perspective page 5 1.3 Optical Isomerism in Clinical Pharmacology page6 1.4 Definition of Enantioselectivity pageT I .5 Enantioselective Pharmacodynamics page 8 1 .6 Enantioselective Pharmacokinetics page 10 1.6.1 Absorption page 11 1.6.2 Distribution page 11 1.6.3 Metabolism page 13 1.6.4 Excretion page 16 1.7 Comment page 17 Chopter 2 Keloprofen: A Review of the lilerolure page 19 2.1 Physicochemical Properties of Ketoprofen page 19 2.2 Clinical Pharmacology of Ketoprofen page 19 2.2.1 Mechanisms of Action of NSAIDs (General) page2l 2.2.2 Mechanism of Action of Ketoprofen page25 2.2.3 Therapeutic Indications of Ketoprofen page26 2.2.4 Advetse Effects of Ketoprofen page29 2.3 Clinical Pharmacokinetics of Ketoprofen page 30 2.3.1 Absorption of Ketoprofen page3l 2.3.2 Distibution Processes of Ketoprofen page32 2.3.3 Metabolism and Excretion of Ketoprofen page34 2.3.4 Factors Which Alter the Pharmacokinetics of Ketoprofen page37 2.3.4.1 Disease State Influences page37 2.3.4.2 Pharmacokinetic Drug Interactions page39 2.3.5 Comment page 4l ul Chopter 3 Acyl-Glucuronides: The lnfluence of Opticol lsomerism page 42 3.1 Acyl-Glucuronide Structure and Isomerism page 43 3 .2 Enantioselective Acyl-Glucuronidation page M 3.3 Intramolecular Reanangement and Hydrolysis of Acyl-Glucuronides page 46 3.4 Generation of Covalent Drug-Protein Adducts page 49 3.5 Clinical Implications of Reversible Acyl-Glucuronidation page 52 Chopter 4 Enonlioselective Anolysis of Ketoptofen in Plosmo by High- Performqncê Liquid Chromotogrophy page 57 4.1 Introduction page 57 4.1.1 Analysis of Enantiomers in Biological Matrices page 57 4.1 .2 Enantioselective Analysis of Ketoprofen page 6l 4.2 Matenals and Methods page 63 4.3 Results and Discussion page 66 Chopter 5 Plosmo Protein Binding of Ketoprofen Enonliomers ¡n Mon: Method Developmenl ond its Applicotion pasezt 5.1 Introduction pageTl 5.2 Materials and Methods Page72 5.3 Results and Discussion Page 78 Chopter ó Stereoselective lnteroctions of Keloptofen Glucuronides w¡lh Humon Plosmo Protein ond Serum Albumin page 88 6.1 Introduction page 88 6.2 Matenals and Methods page 89 6.3 Results page 95 6.4 Discussion page 105 ChopTer 7 Enontioselective Phormocodynomics of Ketoprofen: In Vilro lnhibition of Humon Plotelet Cyclo-Oxygenose Aclivity page 110 7.1 Introduction page 110 7.2 Mateials and Methods page 111 7.3 Results page 115 7.4 Discussion page 118 lv Chopler I The Influence of Renol Funclion on the Enonlioseleclive Phormocokinetics ond Phormocodynomics of Keloprofen in Pqlienls with Rheumoloid ArthÍtis pase t22 8.1 Introduction Page I22 8.2 Methods Page 124 8.3 Results page 130 8.4 Discussion page 153 Chqpter 9 Genelql Conclusion page 160 Appendix page 164 Bibliogrophy page 180 Published Monuscripls Abslroct . Ketoprofen is a chiral nonsteroidal anti-inflammatory drug which is marketed for clinical use as a racemic mixture. It is predominantly eliminated, in man, as acyl-glucuronides in urine. To examine aspects of the potential enantioselective pharmacokinetics and pharmacodynamics of this drug in humans, methods were developed for quantifying total (bound plus unbound) and unbound ketoprofen enantiomers in plasma. Both (R)- and (S)-ketoprofen were extensively (>99Vo) bound to plasma protein. In healthy young volunteers, in vitro studies showed there to be no difference between the unbound fractions in plasma of the ketoprofen enantiomers. Further, at clinically relevant total drug concentrations in plasma, the unbound fraction of each enantiomer was independent of concentration and was not influenced by the presence of either its optical antþode or the acylJinked glucuronide metabolites of ketoprofen. In vitro studies were conducted with the biosynthetic (R)- and (S)-ketoprofen glucuronides to assess the hydrolysis, realrangement and reversible protein binding of these conjugates in a variety of incubation media. It was apparent that albumin, rather than plasma esterases, catalysed (stereoselectively) the hydrolysis of the conjugates and moreover, from the nature of the observed stereoselective protein binding, it appeared that separate binding and catalytic sites were situated on the albumin molecule for these metabolites. In protein-free incubation media at physiological pH and temperature, rearrangement of the acyl- glucuronides to positonal conjugate isomers predominated quantitatively, over the deconjugation reaction for both (R)- and (S)-ketoprofen glucuronides. The pharmacodynamics (antþlatelet effects) of ketoprofen enantiomers were assessed iz vitro, by monitoring the inhibition of thromboxane B, (TXB) generation during controlled blood clotting. There was a close relationship between the concentration of serum unbound (S)-ketoprofen and the degree of inhibition of cyclo-oxygenase, according to a sigmoidal concentration-effect model. (R)-Ketoprofen was devoid of such activity and did not modify the potency of its optical antipode. a Single oral doses of racemic ketoprofen were administered to fifteen elderly patients with rheumatoid arthritis and varying degrees of renal impairment. Both the pharmacokinetics and pharmacodynamics of ketoprofen enantiomers, and the influence thereon of renal function, were assessed in these patients. Significant negative correlations were observed between the area under the plasma concentration-time profile and creatinine clearance, for both total and unbound (S)-ketoprofen. Corresponding significant relationships were also observed for total and unbound (R)-ketoprofen. In vitro studies conducted with pre-dose blood from these patients (alt of whom were receiving concurrent medication) revealed: (i) a higher unbound fraction in plasma for (S)-ketoprofen compared to the corresponding value for (R)-ketoprofen, (il) a concentration-dependent unbound fraction for the (S)- enantiomer of ketoprofen and (üi) a lack of correlation between the unbound concentration of (S)-ketoprofen in serum required to inhibit platelet TXB2 generation by 50Vo (ECro) and creatinine clearance. It was concluded from this clinical study, that diminished renal function was associated with an increased exposure to pharmacologically active unbound (S)-ketoprofen. This was postulated to be due to regeneration of parent aglycone arising from the hydrolysis of systemically accumulated acyl-linked conjugates. And further, it was concluded that the apparent sensitivity of platelet cyclo-oxygenase to the inhibitory effect of unbound (S)-ketoprofen was not influenced by renal function. vl Declorolion I declare that this thesis contains no material which has been accepted for the award of any other degree or diploma in any University and that, to the best of my knowledge and belief, this thesis contains no material previously published or written by another person, except where due reference is made in the toxt of the thesis. I consent to this thesis being made available for photocopying and loan when deposited in the University Library. Peter John Hayball vll Acknowledgemenls To Roger Nation of the School of Pharmacy at the University of South Australia and Felix Bochner of the Department of Clinical and Experimental Pharmacology at the University of Adelaide, I wish to express my sincere gratitude for supervising my Ph.D. studies and providing me with encouragement and guidance throughout this time. I am indebted to Frank May and the staff of the Pharmacy Department at the Repatriation General Hospital for the opportunity of pursuing my studies whilst employed at this institution, and to the Department of Veteran Affairs of the Commonwealth of Australia for providing a research grant which provided funds for conducting these studies. In addition, I would like to express my thanks to Lloyd Sansom of the School of Pharmacy at the Universtty of South Australia for his guidance during initiation of the clinical study (Chapter 8) and Michael Ahern and Malcolm Smith both of the Division of Medicine at the Repatriation General Hospitat for recruiting rheumatoid arthritic patients. I am also grateful to Ralph Massy-Westropp, David Hamon and Josie Newton of the Department of Organic Chemistry at the University of Adelaide for the synthesis of radiolabelled racemic ketoprofen, asymmetric synthesis of ketoprofen enantiomers, optical purity determination of (S)-1- phenylethylamine and assistance with the spectroscopic verification of ketoprofen acyl- glucuronide structure. I would also like to thank Elizabeth Duncan of the South Ausftalian Institute of Medical and Veterinary Science for performing the serum thromboxane B, determinations, Richard Le Leu for technical assistance during the development of the enantioselective assay for total ketoprofen and Donna Lapins of the Repatriation General Hospital for secretarial assistance in the preparation of the thesis. Finally, I would like to express my deepest gratitude to my wife Frances for her constant encouragement and understanding, and to my famity for their continued interest and support. vlll Publicotions
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