Drug disposition: to phenotype or genotype
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INTERNATIONAL JOURNAL OF PHARMACEUTICAL MEDICINE 2001, 15:70–73
REPORT ......................................................................................................................................................................
Drug disposition: to phenotype or genotype Maurice Dickins and Geoff Tucker Pharmacokinetic Sub-group, Pharmacogenetics Working Party
Introduction The promise of ‘precision prescriptions’, provided by the use of genetic information on individual patients, is receiving increased attention, as indicated by reviews in both general medical journals [1–3] and in the lay press [4,5]. It is thought that knowledge of the genetic makeup of a patient with respect to pharmacokinetic (PK) and pharmacodynamic (PD) determinants will provide an indication of how that patient will respond to a particular drug. The remit of this sub-group is to review the impact of genetic variability on PK behaviour and its implications for drug development and use.
Potential consequences of genetic polymorphism in PK processes The potential consequences of genetic polymorphism in PK processes for individuals who lack a functional protein (enzyme/ transporter) include either adverse reactions or lack of response associated with ‘normal’ doses, and lack of pro-drug activation and dependence on alternative routes of elimination which may also be compromised (e.g. by renal impairment, drug–drug or drug–food interactions). Depending upon how the polymorphism affects systemic drug exposure, these individuals may also require either very low or very high doses for effective therapy, thereby imposing a wide choice of dosage on manufacturer and prescriber. Despite great expectations for the future, it is important to recognize that currently knowledge of genotype alone cannot account for PK behaviour in most cases. The PK consequences of the activity of a polymorphic enzyme, for example, depend upon whether it mediates metabolism of the parent drug or primary metabolite or both, the overall contribution to clearance from the affected pathway, the potency of the active moieties, and the patency of competing pathways of elimination. In turn, whether significant PK differences arising from the polymorphism translate into relevant alterations in PD depends on the operating region of the concentration – response relationship, therapeutic index and utility, and whether kinetic variability is
INTERNATIONAL JOURNAL OF PHARMACEUTICAL MEDICINE
outweighed by variability in receptor sensitivity or number, or in the turnover of a natural receptor ligand [6,7]. It is particularly important to appreciate that intrinsic PD variability is often as great, if not greater, than that in PK [8]. In turn, whether PK– PD variability translates into clinically relevant differences in drug response depends on further issues including compliance, the availability of alternate drugs and doctor/patient perception of side-effects.
PK phenomena that exhibit marked genetic polymorphism Single nucleotide polymorphisms (SNPs) of relevance to drug
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