Genetic factors contribute to the phenotype of drug response. We systematically analyzed all available pharmacogenetic data from Medline databases on the impact that genetic polymorphisms have on positive and adverse reactions to antidepressants and antipsychotics. Additionally, dose adjustments that would compensate for genetically caused differences in blood concentrations were calculated. To study pharmacokinetic effects, data for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at least doubling of the dose in extensive metabolizers in comparison to poor metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of relevance. To study the effects of genetic variability on pharmacodynamic pathways, we reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the most part reveal significant associations between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions. In addition associations found in one study could not be replicated in other studies. For this reason, it is not yet possible to translate pharmacogenetic parameters fully into therapeutic recommendations. At present, antidepressant and antipsychotic drug responses can best be explained as the combinatorial outcome of complex systems that interact at multiple levels. In spite of these limitations, combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of relevance might contribute to identify genotypes associated with best and worst responders and they may also identify susceptibility to adverse drug reactions.

Codeine is an analgesic drug acting on m-opiate receptors predominantly via its metabolite morphine, which is formed almost exclusively by the genetically polymorphic enzyme cytochrome P450 2D6 (CYP2D6). Whereas it is known that individuals lacking CYP2D6 activity (poor metabolizers, PM) suffer from poor analgesia from codeine, ultra-fast metabolizers (UM) due to the CYP2D6 gene duplication may experience exaggerated and even potentially dangerous opioidergic effects and no systematical study has been performed so far on this question. A single dose of 30 mg codeine was administered to 12 UM of CYP2D6 substrates carrying a CYP2D6 gene duplication, 11 extensive metabolizers (EM) and three PM. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism methods and a single-base primer extension method for characterization of the gene-duplication alleles. Pharmacokinetics was measured over 24 h after drug intake and codeine and its metabolites in plasma and urine were analyzed by liquid chromatography with tandem mass spectrometry. Significant differences between the EM and UM groups were detected in areas under the plasma concentration versus time curves (AUCs) of morphine with a median (range) AUC of 11 (5-17) mg h l À1 in EMs and 16 (10-24) mg h l À1 in UM (P ¼ 0.02). In urine collected over 12 h, the metabolic ratios of the codeine þ codeine-6-glucuronide divided by the sum of morphine þ its glucuronides metabolites were 11 (6-17) in EMs and 9 (6-16) in UM (P ¼ 0.05). Ten of the 11 CYP2D6 UMs felt sedation (91%) compared to six (50%) of the 12 EMs (P ¼ 0.03). CYP2D6 genotypes predicting ultrarapid metabolism resulted in about 50% higher plasma concentrations of morphine and its glucuronides compared with the EM. No severe adverse effects were seen in the UMs in our study most likely because we used for safety reasons a low dose of only 30 mg. It might be good if physicians would know about the CYP2D6 duplication genotype of their patients before administering codeine.

The gene coding for the cytochrome P450 (CYP) enzyme 2C9 (CYP2C9) carries numerous inherited polymorphisms. Those coding for R144C (*2) and I359L (*3) amino acid substitutions have both significant functional effects and appreciable high population frequencies, and their in vivo consequences have been studied in humans with regard to drug metabolism. This review summarizes present knowledge about the pharmacokinetics, drug responses, and outcomes of clinical studies in individuals with different CYP2C9 genotypes. Tentative estimates of how CYP2C9 genotyping might be applied to dose adjustments in clinical therapy were based on dose-related pharmacokinetic parameters such as clearance or trough drug concentrations. Mean clearances in homozygous carriers of the *3 allele were below 25% of that of the wild type for S -warfarin, tolbutamide, glipizide, celecoxib, and fluvastatin. In the more frequent heterozygous carriers (genotype *1/*3), the clearances were between 40% and 75%. In these cases in which individual dosages are derived from clinical drug effects, such as for the oral anticoagulants, the pharmacogenetics-based dose adjustments showed a good correlation with the genotype-specific empirically derived doses. In addition to its role in pharmacokinetics, CYP2C9 contributes to the metabolism of fatty acids, prostanoids, and steroid hormones, and it may catalyze potentially toxic bioactivation reactions. However, our current understanding of the role of CYP2C9 in biotransformation of endogenous signaling molecules and in drug toxicity is relatively meager.

We have provided preliminary average dose suggestions based on the phenotype or genotype. This is a first attempt to apply the new pharmacogenetics to suggest dose-regimens that take the differences in drug metabolic capacity into account.

Carriers of the CYP2C9 variant *3 had decreased oral clearances of glyburide. This confirms that glyburide is metabolized by CYP2C9. Corresponding differences in insulin plasma levels indicated that dose adjustment based on CYP2C9 genotype may improve antidiabetic treatment.

Bupropion is applied in depression and smoking cessation. Genetic polymorphisms in cytochrome P450 2B6 (CYP2B6) may cause variability in bupropion pharmacokinetics since hydroxylation is known to be mediated by CYP2B6. Bupropion may be a probe drug for CYP2B6 activity in humans. Bupropion pharmacokinetics were studied after a single oral dose of 150 mg in 121 healthy male volunteers. The amino acid polymorphisms R22C, Q172H, S259R, K262R and R487C were analysed by polymerase chain reaction and restriction fragment length polymorphism and plasma concentrations were measured by high-performance liquid chromatography. Pharmacokinetic analysis was performed by non-parametric methods and by population pharmacokinetic modelling. A unimodal distribution of bupropion and hydroxybupropion kinetic parameters was detected with a mean (range) area under the curve (AUC) of 3.64 (0.89-8.14) micromol.h/l for bupropion and 25.5 (6.72-75.3) micromol.h/l for hydroxybupropion. Population kinetic analysis revealed that bupropion total clearance via CYP2B6 alleles *1, *2, *5 and *6 did not differ, but clearance via allele *4 was 1.66-fold higher compared to wild-type allele *1 (P=0.001). Corresponding to the high clearance of bupropion, carriers of the CYP2B6 genotype *1/*4 had significantly higher Cmax of hydroxybupropion compared to all other genotypes (P=0.03). Only a minor fraction of the variability in bupropion and hydroxybupropion kinetics could be explained by the known CYP2B6 amino acid variants, in particular by the CYP2B6*4 allele. The role of this allele should also be studied in other CYP2B6 substrates, including cyclophosphamide, halothane, mianserin, promethazine and propofol.

Phenotyping for drug metabolizing enzymes and transporters is used to assess quantitatively the effect of an intervention (e.g., drug therapy, diet) or a condition (e.g., genetic polymorphism, disease) on their activity. Appropriate selection of test drug and metric is essential to obtain results applicable for other substrates of the respective enzyme/transporter. The following phenotyping metrics are recommended based on the level of validation and on practicability: CYP1A2, paraxanthine/caffeine in plasma 6 h after 150 mg caffeine; CYP2C9, tolbutamide plasma concentration 24 h after 125 mg tolbutamide; CYP2C19, urinary excretion of 4'-OH-mephenytoin 0-12 h after 50 mg mephenytoin; CYP2D6, urinary molar ratio debrisoquine/4-OH-debrisoquine 0-8 h after 10 mg debrisoquine; and CYP3A4, plasma clearance of midazolam after 2 mg midazolam (all drugs given orally).

The present meta-analysis provides quantitative estimates on clinical potency of individual PPIs that may be helpful when switching between PPIs and for assessing the cost-effectiveness of specific PPIs. However, our estimates must be viewed with caution because only a limited dose range has been tested and not exactly the same study conditions were applied for the different substances.