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Pharmacogenetics of taste: turning bitter pills sweet? Poor palatability of oral drug formulations used for young children negatively influences medication intake, resulting in suboptimal treatment. Some children are more sensitive to bitter tastes than others. Bitter tasting status is currently assessed by phenotyping with 6-n-propylthiouracil (PROP) as a bitter probe. Recent studies showed that interindividual differences in PROP sensitivity can be largely explained by three SNPs in TAS2R38, encoding a bitter taste receptor. Gustin, involved in the development of taste buds, and the sweet receptor genotype potentially explain remaining parts of PROP sensitivity variability. Other TAS2 receptor bitter receptor genes may also play a role in bitter aversions. Dependent on their genotype, children may have different medication formulation preferences. Taste genetics could improve drug acceptance by enabling better-informed choices on adapting oral formulations to children’s taste preferences. This paper presents an overview of recent findings concerning bitter taste genetics and discusses these in the context of pediatric drug formulation. KEYWORDS: 6-n-propylthiouracil n children n medication adherence pharmacogenetics n PROP n taste
n
Palatability of oral drug formulations is one the most important determinants of compliance in young children [1,101]. Almost all active pharmaceutical ingredients taste bitter and/or irritate the mouth and throat [1]. Pediatricians as well as parents indicate that poor palatability, due to the bitter taste of active pharmaceutical ingredients, negatively affects compliance and completion of a drug prescription regimen in young children (i.e., 50 drug labels that include pharmacogenetic information and
10.2217/PGS.13.229 © 2014 Future Medicine Ltd
Pharmacogenomics (2014) 15(1), 111–119
Mariëlle J Nagtegaal1,2, Jesse J Swen*2, Lidwien M Hanff3, Kirsten JM Schimmel2 & Henk-Jan Guchelaar2 Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht, The Netherlands 2 Leiden University Medical Centre, Department of Clinical Pharmacy & Toxicology, PO Box 9600, NL 2300 RC Leiden, The Netherlands 3 Erasmus University Medical Centre, Department of Hospital Pharmacy, Rotterdam, The Netherlands *Author for correspondence: Tel.: +31 71526 2790 Fax: +31 71 524 8101 [email protected] 1
part of
ISSN 1462-2416
111
Review
Nagtegaal, Swen, Hanff, Schimmel & Guchelaar
this number is likely to increase in the near future [11]. However, the genetics of taste has not often been investigated in the pharmaceutical field, even though it could have significant implications in the acceptance of drugs and compliance to drugs, especially in children. Adapting oral formulations to children’s preferences and needs based on their genotype presents a novel approach in personalized medicine. The aim of this paper is to present an overview of recent findings concerning bitter taste genetics and to discuss these findings in the context of the use of oral medication in children.
Taste & compliance Compliance in drug therapy is the extent to which a patient properly follows medical advice. Ignoring or not following a prescription regimen is called noncompliance and can adversely affect an individual’s therapeutic response [13,101]. There are many reasons for noncompliance in (young) children, the main ones are the frequency and difficulty of the dosing regimen, side effects and poor taste [101]. The taste of a drug has been directly related to the patient’s acceptability and compliance of the prescribed drug [13]. Moreover, taste is the key element by which young children determine food and drug acceptance [1,3]. Rejecting bitter-tasting products is a strong innate response. This phenomenon serves an important biological function: bitter taste perception is the protective mechanism that prevents from ingesting structurally distinct toxins and/or inedible materials [3,14]. However, in medicine this innate response can be troublesome. Taste plays an important role in ensuring successful administration of a medicine and compliance in children [14]. The importance of drug palatability is stressed by a recently published review paper that concludes that evaluation of palatability and taste should be included in the review process before European marketing authorization is granted, preferably in the form of a pediatric investigation plan [13]. The palatability of an orally administrated drug can be improved by encapsulating the bitter drug substance in capsules or tablets. As described in an excellent review by Mennella et al. [14], this method is problematic for (young) children since they are unable, and sometimes refuse, to swallow capsules or tablets, causing the risk of choking. The inability of children to swallow capsules or tablets can be overcome by crushing or splitting the tablets, but may result in increased taste problems, dosing inaccuracies, 112
Pharmacogenomics (2014) 15(1)
as well as altered bioavailability [14,15]. In addition, tablets or capsules containing the adequate pediatric dosage are often not commercially available. As a result, the rejection of bitter tasting medication and the lack of child-friendly formulations leads to a suboptimal treatment and noncompliance of young children [1,16,101]. Many pediatric drugs are administered as liquid oral formulations, which allow convenient dose adjustment, but masking or covering of the unpalatable ingredients can be difficult [13,14]. A commonly used method is the addition of sweeteners to oral liquid medication. This method may be problematic for dietary reasons [14]. More palatable medication formulations for children may be achieved by a better understanding of the biology of bitter taste perception. Therefore, we present a brief overview of the pharmacology of bitter taste perception, and the use of different methods to assess taste preferences is addressed.
Pharmacology of taste Taste-receptor cells (TRCs) are specialized epithelial cells embedded into taste buds, which are mainly found in different (circumvallate, foliate and fungiform) papillae present in all areas of the tongue. Microvilli, projected by TRCs to the apical surface of the taste bud, form the taste pore. Taste molecules interact with this site of action in a ‘lock-and-key’ mechanism after dissolving in saliva. Bitter tastes are detected in fungiform papillae (FP), which are present mostly at the dorsal surface of the tongue [3]. The TRCs in the FP are innervated by the facial nerve [17]. As described in a review by Chandrashekar et al., individual TRCs can express different types of taste receptors, so that taste experience is the result of the decoding of the combined activity of the various TRCs (the socalled ‘across-fibre pattern’ of coding) [3]. Furthermore, specific neural pathways are excited, and olfactory, visual and memory are processed simultaneously. Prior experience can therefore to some degree influence taste perception, stressing the importance of avoiding a negative taste experience when taking oral medication [13]. The perception of sweet, umami and bitter tastes is mediated by a small family of three G-protein-coupled receptors (GPCRs), known as the TAS1 receptors (T1Rs; T1R1, T1R2 and T1R3) and a large family of TAS2 receptors (T2Rs), including TAS2R38. These GPCRs are found in heterodimeric and homodimeric receptor complexes. T1Rs are expressed in heterodimeric TRC complexes, and define two cell types: future science group
Pharmacogenetics of taste
TRCs expressing both T1R1 and T1R3 (umami taste perception) and TRCs coexpressing T1R2 and T1R3 (sweet taste perception) [3]. A substantial larger family of GPCRs, the T2R receptors (n = 26), constitute the bitter receptors, which are in a homodimeric receptor complex. While all other taste receptor genes could be expressed together in one TRC, bitter taste receptors are selectively expressed in the same TRC subsets [3]. There are many bitter receptors, because each of the T2Rs is likely to be narrowly tuned and selectively sensitive to one compound or a few structurally related bitter compounds [3,17]. For instance, the TAS2R38 receptor responds to PROP, a drug prescribed for hyperthyroidism [1,3].
Methodologies to assess taste preferences When performing taste preference tests in children, two aspects have to be taken into account – the sensitivity of the subject to the tastant and the hedonic valence (facial expression by which the pleasure that food gives to an individual is measured) of the taste sensation. Young children cannot distinguish these two different responses: rejection or acceptance ‘automatically’ involve hedonics [13,14]. Thus, young children are not yet capable to report their taste preference properly, as acknowledged by an EMA report [13,102]. The distinction between these two aspects in children >5 years is usually unequivocal and these older children are therefore frequently used to assess taste preferences [14]. As outlined in Table 1, PROP taster status can be determined in children by three different tests: the forced-choice, paired-comparison tracking technique [18], the forced-choice procedure with like/dislike categories [19] and hedonic rating scales [13]. The forced-choice methods are standardized in adults [18,20], but not validated in children [14]. Although testing children directly is the most obvious approach to test bitter-masking excipients or other more palatable drug formulations, there is one limitation: inclusion of children in nontherapeutic studies is considered unethical [21]. As described by Mennella et al., specifically trained adult sensory test panels can be used to test palatability of oral drug formulations for the pediatric market. Adults are easy to instruct and can express their taste preferences properly [14]. However, as outlined later, age can affect differences in the responses to (bitter) tastes [22]. This implicates that the use of adult sensory panels should be well considered, as it is not suitable for every purpose. future science group
Review
A recently developed method to evaluate taste is the electronic tongue (E-Tongue). This method assesses tastes objectively by measuring the electric potential of drug solutions [13,14]. The E-Tongue is has many advantages because of its speed, relatively low costs and lack of the need to expose test subjects to a drug substance. However, these systems also have limitations because they do not use biological receptors. As a result, the E-Tongue is only suitable for measuring the intensity of the taste of the solution, and not for processes altering biological systems [14].
Bitter taste genetics One of the most intensively studied bitter receptor genes is TAS2R38 (accession no. NM_176817). The TAS2R38 gene consists of a single exon that is 1002 bp long and encodes a 333-amino acid 7-transmembrane domain, guanine nucleotidebinding protein-coupled receptor [23]. Homozygosity of the TAS2R38 gene is associated with extremes of PROP sensitivity (nontasters or supertasters) whereas heterozygosity is associated with a larger tolerability of bitter sensitivity (tasters) [8,19,23]. These are the early data, which showed that PTC sensitivity is a classical Mendelian recessive trait; nontasters have two recessive alleles (tt) while tasters have at least one dominant allele (T). Genotypes of the TAS2R38 locus are thus likely to be predictive of a large proportion of the interindividual differences of PROP sensitivity. Bartoshuk et al. subdivided the taster group into medium tasters and supertasters, as there is a wide range of sensitivity for bitterness among PROP tasters [24]. Supertasters report fixed concentration of sucrose, sodium chloride, citric acid and quinine as more intense as compared with ‘medium’ tasters. Consequently, individuals who respond with increased sensitivity to all or most of these stimuli, without regard to their genetic sensitivity to PROP, are described as ‘general supertasters’ [25]. Individuals should thus be classified as supertasters, medium tasters or nontasters [25]. A method to distinguish medium tasters from supertasters by a PROP-taster phenotyping test is described by Tepper et al. [26]. Interestingly, Smutzer et al. validated PROP taste strips to rapidly test PROP sensitivity in adults, which may also be potentially used in daily practice in (young) children [27]. A potential problem for assessing bitter tasting status by PROP phenotyping are the high costs and limited availability of pharmaceutical grade 6-n-propylthiouracil that is required when testing in a medical environment. Reed et al. present several hypotheses for the mechanisms behind the ‘supertaster www.futuremedicine.com
113
Review
Nagtegaal, Swen, Hanff, Schimmel & Guchelaar
Table 1. Advantages and disadvantages of some methods used to asses taste preferences in children. Technique
Advantages
Disadvantages
Comments
Forced-choice, pairedcomparison tracking technique [18]
Memory requirements are minimized PROP-sensitivity and preferences are both determined No response bias Standardized method
Many false-negative responses Not useful in large scale population studies
Taste strips containing PROP have been developed that replaces the aqueous solutions used in this method [27]
Forced-choice procedure with like/dislike categories [19,20]
Attractive (funny) method for children Memory requirements are minimized PROP-sensitivity and preferences are both determined
Response bias Many false-negative responses
–
Hedonic rating scales [13]
Useful in young children (
Pharmacogenetics of taste: turning bitter pills sweet? Poor palatability of oral drug formulations used for young children negatively influences medication intake, resulting in suboptimal treatment. Some children are more sensitive to bitter tastes than others. Bitter tasting status is currently assessed by phenotyping with 6-n-propylthiouracil (PROP) as a bitter probe. Recent studies showed that interindividual differences in PROP sensitivity can be largely explained by three SNPs in TAS2R38, encoding a bitter taste receptor. Gustin, involved in the development of taste buds, and the sweet receptor genotype potentially explain remaining parts of PROP sensitivity variability. Other TAS2 receptor bitter receptor genes may also play a role in bitter aversions. Dependent on their genotype, children may have different medication formulation preferences. Taste genetics could improve drug acceptance by enabling better-informed choices on adapting oral formulations to children’s taste preferences. This paper presents an overview of recent findings concerning bitter taste genetics and discusses these in the context of pediatric drug formulation. KEYWORDS: 6-n-propylthiouracil n children n medication adherence pharmacogenetics n PROP n taste
n
Palatability of oral drug formulations is one the most important determinants of compliance in young children [1,101]. Almost all active pharmaceutical ingredients taste bitter and/or irritate the mouth and throat [1]. Pediatricians as well as parents indicate that poor palatability, due to the bitter taste of active pharmaceutical ingredients, negatively affects compliance and completion of a drug prescription regimen in young children (i.e., 50 drug labels that include pharmacogenetic information and
10.2217/PGS.13.229 © 2014 Future Medicine Ltd
Pharmacogenomics (2014) 15(1), 111–119
Mariëlle J Nagtegaal1,2, Jesse J Swen*2, Lidwien M Hanff3, Kirsten JM Schimmel2 & Henk-Jan Guchelaar2 Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht, The Netherlands 2 Leiden University Medical Centre, Department of Clinical Pharmacy & Toxicology, PO Box 9600, NL 2300 RC Leiden, The Netherlands 3 Erasmus University Medical Centre, Department of Hospital Pharmacy, Rotterdam, The Netherlands *Author for correspondence: Tel.: +31 71526 2790 Fax: +31 71 524 8101 [email protected] 1
part of
ISSN 1462-2416
111
Review
Nagtegaal, Swen, Hanff, Schimmel & Guchelaar
this number is likely to increase in the near future [11]. However, the genetics of taste has not often been investigated in the pharmaceutical field, even though it could have significant implications in the acceptance of drugs and compliance to drugs, especially in children. Adapting oral formulations to children’s preferences and needs based on their genotype presents a novel approach in personalized medicine. The aim of this paper is to present an overview of recent findings concerning bitter taste genetics and to discuss these findings in the context of the use of oral medication in children.
Taste & compliance Compliance in drug therapy is the extent to which a patient properly follows medical advice. Ignoring or not following a prescription regimen is called noncompliance and can adversely affect an individual’s therapeutic response [13,101]. There are many reasons for noncompliance in (young) children, the main ones are the frequency and difficulty of the dosing regimen, side effects and poor taste [101]. The taste of a drug has been directly related to the patient’s acceptability and compliance of the prescribed drug [13]. Moreover, taste is the key element by which young children determine food and drug acceptance [1,3]. Rejecting bitter-tasting products is a strong innate response. This phenomenon serves an important biological function: bitter taste perception is the protective mechanism that prevents from ingesting structurally distinct toxins and/or inedible materials [3,14]. However, in medicine this innate response can be troublesome. Taste plays an important role in ensuring successful administration of a medicine and compliance in children [14]. The importance of drug palatability is stressed by a recently published review paper that concludes that evaluation of palatability and taste should be included in the review process before European marketing authorization is granted, preferably in the form of a pediatric investigation plan [13]. The palatability of an orally administrated drug can be improved by encapsulating the bitter drug substance in capsules or tablets. As described in an excellent review by Mennella et al. [14], this method is problematic for (young) children since they are unable, and sometimes refuse, to swallow capsules or tablets, causing the risk of choking. The inability of children to swallow capsules or tablets can be overcome by crushing or splitting the tablets, but may result in increased taste problems, dosing inaccuracies, 112
Pharmacogenomics (2014) 15(1)
as well as altered bioavailability [14,15]. In addition, tablets or capsules containing the adequate pediatric dosage are often not commercially available. As a result, the rejection of bitter tasting medication and the lack of child-friendly formulations leads to a suboptimal treatment and noncompliance of young children [1,16,101]. Many pediatric drugs are administered as liquid oral formulations, which allow convenient dose adjustment, but masking or covering of the unpalatable ingredients can be difficult [13,14]. A commonly used method is the addition of sweeteners to oral liquid medication. This method may be problematic for dietary reasons [14]. More palatable medication formulations for children may be achieved by a better understanding of the biology of bitter taste perception. Therefore, we present a brief overview of the pharmacology of bitter taste perception, and the use of different methods to assess taste preferences is addressed.
Pharmacology of taste Taste-receptor cells (TRCs) are specialized epithelial cells embedded into taste buds, which are mainly found in different (circumvallate, foliate and fungiform) papillae present in all areas of the tongue. Microvilli, projected by TRCs to the apical surface of the taste bud, form the taste pore. Taste molecules interact with this site of action in a ‘lock-and-key’ mechanism after dissolving in saliva. Bitter tastes are detected in fungiform papillae (FP), which are present mostly at the dorsal surface of the tongue [3]. The TRCs in the FP are innervated by the facial nerve [17]. As described in a review by Chandrashekar et al., individual TRCs can express different types of taste receptors, so that taste experience is the result of the decoding of the combined activity of the various TRCs (the socalled ‘across-fibre pattern’ of coding) [3]. Furthermore, specific neural pathways are excited, and olfactory, visual and memory are processed simultaneously. Prior experience can therefore to some degree influence taste perception, stressing the importance of avoiding a negative taste experience when taking oral medication [13]. The perception of sweet, umami and bitter tastes is mediated by a small family of three G-protein-coupled receptors (GPCRs), known as the TAS1 receptors (T1Rs; T1R1, T1R2 and T1R3) and a large family of TAS2 receptors (T2Rs), including TAS2R38. These GPCRs are found in heterodimeric and homodimeric receptor complexes. T1Rs are expressed in heterodimeric TRC complexes, and define two cell types: future science group
Pharmacogenetics of taste
TRCs expressing both T1R1 and T1R3 (umami taste perception) and TRCs coexpressing T1R2 and T1R3 (sweet taste perception) [3]. A substantial larger family of GPCRs, the T2R receptors (n = 26), constitute the bitter receptors, which are in a homodimeric receptor complex. While all other taste receptor genes could be expressed together in one TRC, bitter taste receptors are selectively expressed in the same TRC subsets [3]. There are many bitter receptors, because each of the T2Rs is likely to be narrowly tuned and selectively sensitive to one compound or a few structurally related bitter compounds [3,17]. For instance, the TAS2R38 receptor responds to PROP, a drug prescribed for hyperthyroidism [1,3].
Methodologies to assess taste preferences When performing taste preference tests in children, two aspects have to be taken into account – the sensitivity of the subject to the tastant and the hedonic valence (facial expression by which the pleasure that food gives to an individual is measured) of the taste sensation. Young children cannot distinguish these two different responses: rejection or acceptance ‘automatically’ involve hedonics [13,14]. Thus, young children are not yet capable to report their taste preference properly, as acknowledged by an EMA report [13,102]. The distinction between these two aspects in children >5 years is usually unequivocal and these older children are therefore frequently used to assess taste preferences [14]. As outlined in Table 1, PROP taster status can be determined in children by three different tests: the forced-choice, paired-comparison tracking technique [18], the forced-choice procedure with like/dislike categories [19] and hedonic rating scales [13]. The forced-choice methods are standardized in adults [18,20], but not validated in children [14]. Although testing children directly is the most obvious approach to test bitter-masking excipients or other more palatable drug formulations, there is one limitation: inclusion of children in nontherapeutic studies is considered unethical [21]. As described by Mennella et al., specifically trained adult sensory test panels can be used to test palatability of oral drug formulations for the pediatric market. Adults are easy to instruct and can express their taste preferences properly [14]. However, as outlined later, age can affect differences in the responses to (bitter) tastes [22]. This implicates that the use of adult sensory panels should be well considered, as it is not suitable for every purpose. future science group
Review
A recently developed method to evaluate taste is the electronic tongue (E-Tongue). This method assesses tastes objectively by measuring the electric potential of drug solutions [13,14]. The E-Tongue is has many advantages because of its speed, relatively low costs and lack of the need to expose test subjects to a drug substance. However, these systems also have limitations because they do not use biological receptors. As a result, the E-Tongue is only suitable for measuring the intensity of the taste of the solution, and not for processes altering biological systems [14].
Bitter taste genetics One of the most intensively studied bitter receptor genes is TAS2R38 (accession no. NM_176817). The TAS2R38 gene consists of a single exon that is 1002 bp long and encodes a 333-amino acid 7-transmembrane domain, guanine nucleotidebinding protein-coupled receptor [23]. Homozygosity of the TAS2R38 gene is associated with extremes of PROP sensitivity (nontasters or supertasters) whereas heterozygosity is associated with a larger tolerability of bitter sensitivity (tasters) [8,19,23]. These are the early data, which showed that PTC sensitivity is a classical Mendelian recessive trait; nontasters have two recessive alleles (tt) while tasters have at least one dominant allele (T). Genotypes of the TAS2R38 locus are thus likely to be predictive of a large proportion of the interindividual differences of PROP sensitivity. Bartoshuk et al. subdivided the taster group into medium tasters and supertasters, as there is a wide range of sensitivity for bitterness among PROP tasters [24]. Supertasters report fixed concentration of sucrose, sodium chloride, citric acid and quinine as more intense as compared with ‘medium’ tasters. Consequently, individuals who respond with increased sensitivity to all or most of these stimuli, without regard to their genetic sensitivity to PROP, are described as ‘general supertasters’ [25]. Individuals should thus be classified as supertasters, medium tasters or nontasters [25]. A method to distinguish medium tasters from supertasters by a PROP-taster phenotyping test is described by Tepper et al. [26]. Interestingly, Smutzer et al. validated PROP taste strips to rapidly test PROP sensitivity in adults, which may also be potentially used in daily practice in (young) children [27]. A potential problem for assessing bitter tasting status by PROP phenotyping are the high costs and limited availability of pharmaceutical grade 6-n-propylthiouracil that is required when testing in a medical environment. Reed et al. present several hypotheses for the mechanisms behind the ‘supertaster www.futuremedicine.com
113
Review
Nagtegaal, Swen, Hanff, Schimmel & Guchelaar
Table 1. Advantages and disadvantages of some methods used to asses taste preferences in children. Technique
Advantages
Disadvantages
Comments
Forced-choice, pairedcomparison tracking technique [18]
Memory requirements are minimized PROP-sensitivity and preferences are both determined No response bias Standardized method
Many false-negative responses Not useful in large scale population studies
Taste strips containing PROP have been developed that replaces the aqueous solutions used in this method [27]
Forced-choice procedure with like/dislike categories [19,20]
Attractive (funny) method for children Memory requirements are minimized PROP-sensitivity and preferences are both determined
Response bias Many false-negative responses
–
Hedonic rating scales [13]
Useful in young children (
