Abstract

INTRODUCTION

Functional dyspepsia (FD) and gastroesophageal reflux disease (GORD) are associated with significantly increased healthcare costs related to doctor visits, diagnostic examinations, and therapeutic procedures, and a reduced quality of life. ^{1 , 2} The prevalence of GORD worldwide is 13.3%, and in Europe is from 15% to 19.1%, ³ whereas the global prevalence of uninvestigated FD is from 6.9% to 17.6%. ⁴ In Spain, 9.8% of the population manifests typical symptoms of GORD more than once a week, as well as dyspeptic symptoms (39% of patients present it at some time throughout their life). ^{5 , 6}

Cinitapride (4‐amino‐N‐[1‐(3‐cyclohexen‐1‐yl‐methyl)‐4‐piperidinyl]‐2‐ethoxy‐5 nitrobenzamide) is a gastrointestinal prokinetic drug, developed and commercialized in Spain in 1989. It is prescribed for the treatment of FD, and as an adjuvant therapy for GORD. ⁷ Due to its procholinergic/serotoninergic activity, cinitapride increases the tone of the lower esophageal sphincter with a potent gastrokinetic effect, generating significant evacuation of the bowel. It is also a D2 receptor antagonist which can contribute to the prokinetic effect. ⁸ The frequencies of some adverse drug reactions (ADRs) are not entirely known, being similar among benzamides. Consistent with its mechanism of action, neurological disorders related to extrapyramidal symptoms (neck, tongue, and face muscle spasm), somnolence (with a prevalence of 0.1% to 1%), gynecomastia, galactorrhea, skin and subcutaneous tissue disorders like rash, pruritus, and angioedema, are described in the drug label. ^{7 , 9} Cinitapride is marketed in India, Pakistan, Peru, Argentina, Paraguay, Uruguay, Mexico, Costa Rica, Guatemala, Honduras, Nicaragua, Panama, and El Salvador. ¹⁰

Cinitapride undergoes significant hepatic first‐pass metabolism. More than 70% of an oral dose is rapidly absorbed and metabolized by the isoforms of the cytochrome P450 (CYP), CYP3A4 and CYP2C8. ⁷ After 1 mg single oral dose, cinitapride's area under the curve from 0 to 24h (AUC_0–t ) was from 1580 to 3464pg*h/ml, while C_max ranged between 330 and 1398pg/ml. ^{8 , 11 , 12}

For cinitapride, the lack of articles describing its pharmacogenetics and the absence of clinical guidelines indicates the importance of further research in this area. Likewise, CYP2C8 (the gene coding for CYP2C8) is poorly characterized; Indeed, the impact of CYP2C8 alleles on the enzyme's function is not clearly known. ^{13 , 14 , 15} Therefore, the assessment of their function on a well‐known substrate such as cinitapride represents a valuable model which may be extended to other substrates.

The aim of this candidate gene study was to describe relevant pharmacogenetic biomarkers for cinitapride prescription. In this regard, we aimed to confirm the impact of relevant variants in CYP3A4 and CYP2C8 (i.e., the principal candidate genes) along with demographic characteristics on cinitapride's pharmacokinetics and safety and to evaluate the impact of CYP2C8 alleles on the enzyme's function. Furthermore, we aimed to evaluate in an exploratory manner other variants in other relevant pharmacogenes (i.e., secondary candidates). The reason for including single nucleotide polymorphisms (SNPs) in genes apparently unrelated to cinitapride was the scarcity of information included in its drug label and previous literature. This work is promoted by La Princesa University Hospital Multidisciplinary Initiative for the Implementation of Pharmacogenetics, PriME‐PGx. ¹⁶

MATERIALS AND METHODS

RESULTS

Pharmacokinetics

Mean AUC_0–t was lower for men (total = 3447.35 ± 1261.56h*pg/ml, 2764.08±1264.76h*pg/ml for men, 4078.06 ± 904.94h*pg/ml for women; p = 0.005) and similar for Caucasians and Latin Americans (3505.33± 1387.17h*pg/ml and 3401.79±1205.37h*pg/ml, respectively; p = 0.829). Mean C_max was 980.80± 388.93h*pg/ml lower for men than women (858.90± 463.96h*pg/ml vs. 1093.33±276.84h*pg/ml, respectively; p = 0.042) and similar for Caucasians and Latin Americans (1010.05±357.83h*pg/ml Caucasians vs. 957.82±423.65h*pg/ml Latin Americans; p = 0.578). After DW correction, no significant differences were found for either AUC/DW or C_max/DW and other pharmacokinetic parameters concerning sex and race (Table 3).

TABLE 3

Cinitapride pharmacokinetic parameters based on sex and race

	N	AUC/DW (kg*h*pg/ml*mg)		Cmax/DW (kg*pg/ml*mg)		t max (h)		t 1/2 (h)		Vd/F (L/kg)		Cl/F (L/h*kg)
		Mean	SD	Mean	SD	Mean	SD	Mean	SD	Mean	SD	Mean	SD
Sex a
Male	12	211,346.15	114,436.22	64,158.91	34,207.46	0.78	0.11	57.92	33.78	505.52	373.76	6.12	3.08
Female	13	270,792.58	86,889.98	71,585.16	22,121.53	0.84	0.10	50.66	9.95	302.42	131.11	4.15	1.57
Total	25	242,258.29	103,421.06	68,020.56	28,201.75	0.81	0.10	54.15	24.21	399.91	288.70	5.10	2.56
Race a
Caucasian	11	266,267.96	126,378.82	75,783.44	30,633.93	0.81	0.07	61.45	34.89	430.94	368.04	4.72	2.31
Latin American	14	223,393.56	81,175.26	61,921.16	25,600.52	0.82	0.13	48.41	8.06	375.53	219.59	5.39	2.80
Total	25	242,258.29	103,421.06	68,020.56	28,201.75	0.81	0.10	54.15	24.21	399.91	288.70	5.10	2.56

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Abbreviations: AUC, area under the curve; C_max, maximum concentration_; CI/F, drug clearance adjusted for bioavailability; DW, dose/weight ratio; SD, standard deviation; t _1/2, time to reach half maximum concentration; t _max, time to reach maximum concentration; Vd/F, volume of distribution adjusted for bioavailability.

^a No significant relationships were observed after univariate and multivariate analysis.

Table 4 shows the significant relationships observed between genotyped variants or phenotypes and cinitapride pharmacokinetic parameters. Subjects with CYP2C8 *1A/*3 and *3/*3 genotypes showed significantly lower cinitapride AUC/DW and C_max/DW compared to subjects with the *1A/*1A genotype (decrease of 42% and 35% and p= 0.003, p= 0.011, respectively) and with the *1A/*4 genotype carriers (p = 0.004, p = 0.002, respectively). Likewise, *1A/*4 genotype showed a tendency towards higher AUC/DW and C_max/DW compared to *1A/*1A genotype (p= 0.422 and p= 0.097). Conversely, significantly higher values of Vd/F _W and Cl/F _W were observed in subjects with CYP2C8 *1A/*3 and *3/*3 genotypes compared to those with *1A/*1A (p <0.001, p = 0.003, respectively) and *1A/*4 diplotypes (p = 0.001, p = 0.004, respectively). In the case of the comparison between *1/*1 and *1A/*4, AUC/DW and C_max/DW values were 45% and 63% higher in *1A/*4, although these differences did not reach statistical significance (p= 0.422 and p= 0.097, respectively). Furthermore, CYP2C9 normal metabolizers (NMs) showed significantly higher AUC/DW, C_max, and t _max and significantly lower Vd/F and Cl/F compared to CYP2C9 intermediate (IM) andpoor (PM) metabolizers (p = 0.002, p = 0.003, p = 0.038, p <0.001, and p = 0.002, respectively). No significantly differences were found between CYP3A4 normal (NMs, n = 23) and intermediate (IMs, n = 2) metabolizers either in AUC/DW and C_max/DW (p = 0.719 and p = 0.523, respectively) or in the rest of the pharmacokinetics parameters.

TABLE 4

Cinitapride pharmacokinetic parameters based on genotypes or phenotypes showing statistically significant variability in the univariate analysis

Genotype or phenotype		N	AUC/DW (kg*h*pg/ml*mg)		Cmax/DW (kg*pg/ml*mg)		t max (h)		t 1/2 (h)		Vd/F (L/kg)		Cl/F (L/h*kg)
			Median	SD	Median	SD	Median	SD	Median	SD	Median	SD	Median	SD
CYP2C8 a	*1A/*1A	12	280,762.57	85,231.95	75,673.43	23,803.30	0.85	0.11	48.62	10.43	261.62	62.80	3.91	1.13
	*1/*3 +*3/*3	10	162,863.15*1	63,250.72	48,951.85*1	14,131.46	0.76	0.07	63.68	35.18	627.35*1	344.41	7.13*1	2.79
	*1/*4	2	403,033.83	40,280.38	124,334.12	6660.84	0.75	0.00	42.40	6.77	151.90	42.41	2.51	0.23
CYP2C9 b	NM	14	293,193.04*	93,972.24	81,663.87*	29,152.95	0.85*	0.11	47.45	10.35	249.25*	73.57	3.78*	1.19
	IM+PM	11	177,432.25	77,041.78	50,656.35	14,549.46	0.76	0.07	62.66	33.54	591.66	347.53	6.76	2.91
CYP1A2*1B	*1/*1	2	214,491.16	65,685.21	55,649.07	7714.45	0.75	0.00	101.71*2	79.59	804.22	777.99	4.94	1.53
	*1/*1B	12	270,460.10	132,861.33	67,668.36	33,308.76	0.80	0.10	53.60	12.32	393.54	279.82	5.13	3.45
	*1B/*1B	11	216,541.25	63,129.07	70,654.14	25,378.17	0.83	0.12	46.10	9.08	333.34	125.55	5.08	1.57
ABCB1 C1236T rs1128503	C/C	10	202,527.12	92,016.32	64,764.72	29,073.89	0.80	0.11	46.57	11.10	395.32	207.06	5.75	2.06
	C/T	12	287,405.91	97,873.86	75,587.37	28,222.68	0.84	0.11	51.39	11.55	287.55*4 a	120.07	4.14	2.40
	T/T	3	194,105.06	118,163.39	48,606.12	19,936.73	0.75	0.00	90.41*3	58.67	864.63	572.84	6.74	4.04
ABCC2 rs2273697	G/G	17	232,045.46	96,946.17	66,551.96	27,286.33	0.81	0.11	47.38*	10.07	346.06	177.17	5.21	2.49
	G/A+A/A	8	263,960.57	119,990.45	71,141.34	31,759.91	0.81	0.10	68.53	37.82	514.34	438.18	4.85	2.87
COMT rs13306278	C/C	17	263,826.22	101,380.57	72,865.07	30,798.21	0.82	0.12	47.77*	10.47	306.75*	170.37	4.59	2.43
	C/T	8	196,426.45	98,228.01	57,725.99	19,511.35	0.80	0.07	67.70	38.08	597.87	391.86	6.17	2.66
SLC22A1*3 rs12208357	*1/*1	22	255,124.99*	99,082.99	69,141.44	24,925.98	0.83	0.10	55.16	25.41	371.61	272.52	4.59*	1.89
	*1/*3	3	147,902.53	100,460.33	59,800.78	53,899.87	0.71	0.07	46.69	12.71	607.42	383.32	8.78	4.27
Total		25	242,258.29	103,421.06	68,020.56	28,201.75	0.81	0.10	54.15	24.21	399.91	288.70	5.10	2.56

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Abbreviations: AUC, area under the curve; C_max, maximum concentration_; CI/F, drug clearance adjusted for bioavailability; DW, dose/weight ratio; IM, intermediate metabolizer; NM, normal metabolizer; PM, poor metabolizer; SD, standard deviation; t _1/2, time to reach half maximum concentration; t _max, time to reach maximum concentration; Vd/F, volume of distribution adjusted for bioavailability.

^a For the CYP2C8 analysis, one *3/*4 subject was excluded.

^b CYP2C9 NM phenotype included *1/*1 diplotype; IM phenotype included *1/*2, *2/*2, and *1/*3 diplotypes; only one volunteer showed the *2/*3 diplotype (PM phenotype).

*p< 0.05 after ANOVA or t‐test; *1 p <0.05 vs. *1/*1 and *1/*4, after ANOVA and Bonferroni post‐hoc test; * 2 p <0.05 vs. *1B/1*B after ANOVA and Bonferroni post‐hoc test; *3 p <0.05 vs. *1/*1; *4 p <0.05 vs. T/T.

Additionally, volunteers carrying the CYP1A2 *1/*1 diplotype were significantly associated with a higher t _1/2 than volunteers with the*1B/*1B diplotype (p = 0.030). Individuals carrying the ABCB1 C1236T T/T genotype presented significantly higher values of t _1/2 and Vd/F _W than those carrying the C/C diplotype (p = 0.020, p = 0.031), while there were no differences in other SNPs of the ABCB1 gene. COMT rs13306278 C/C genotype carriers showed lower t _1/2 (p< 0.040) and Vd/F (p <0.01) in comparison with C/T subjects. SLC22A1*1/*1 individuals presented higher AUC/DW and lower Cl/F than *1/*3 (p = 0.027, p = 0.026, respectively). Finally, individuals with ABCC2 rs2273697 G/G genotype exhibited a lower t _1/2 compared with those with G/A and A/A genotypes (p <0.02). No significant results were observed for variants in the remaining genes.

Regarding multivariate analysis, CYP2C8 *3 genotype and SLC22A1 *3 were significantly related to AUC/DW variability (Table 5); CYP2C8 genotype to C_max/DW variability; CYP2C8 genotype, CYP2C9 phenotype, and ABCB1 C1236T to Vd/F _W; and ABCB1 C1236T to t _1/2 variability; and CYP2C8 genotype and SLC22A1*3 to Cl/F variability. No variables were related to t _max variability (Table 5). After Bonferroni correction for multiple comparisons, only CYP2C8 associations with AUC/DW, C_max/DW, Vd/F, and Cl/F variability and ABCB1 C1236T with Vd/F variability remained significant (i.e., p <0.006).

TABLE 5

Coefficients and significance deriving from the multivariate analysis of pharmacokinetic parameters

Factor		β	R 2	Significance (p)
AUC/DW
CYP2C8 #	*1A/*3 +*3/*3 vs. *1A/*1A+*1A/*4	0.57	0.557	<0.001
SLC22A1*3	*1/*1 vs. *1/*3	−0.44		0.041
Cmax/DW
CYP2C8 #	1A/*3 +*3/*3 vs. *1A/*1A+*1A/*4	0.51	0.376	0.001
t max
No variables related.
t 1/2
ABCB1 C1236T	C/C vs. C/T+T/T	0.507	0.266	0.010
Vd/F
CYP2C8 #	1A/*3 +*3/*3 vs. *1A/*1A+*1A/*4	−1.600	0.71	0.001
ABCB1 C1236T	C/C vs. C/T+T/T	0.933		0.002
CYP2C9	NM vs. IM+PM	−0.936		0.047
Cl/F
CYP2C8 #	1A/*3 +*3/*3 vs. *1A/*1A+*1A/*4	−0.571	0.556	<0.001
SLC22A1*3	*1/*1 vs. *1/*3	0.45		0.041

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Abbreviations: AUC, area under the curve; C_max, maximum concentration; CI/F, drug clearance adjusted for bioavailability; DW, dose/weight ratio; IM, intermediate metabolizer; NM, normal metabolizer; PM, poor metabolizer; t _1/2, time to reach half maximum concentration; t _max, time to reach maximum concentration; Vd/F, volume of distribution adjusted for bioavailability.

^# p <0.006 after Bonferroni correction for multiple comparisons in multivariate analysis.

No adverse event was causally related to cinitapride intake; therefore, no ADR was noted. Therefore, the effect of ADRA2A, HTR2A, HTR2C, DRD2, and DRD3 (genes potentially involved in cinitapride pharmacodynamics) polymorphism could not be evaluated concerning cinitapride's tolerability nor the impact of the remaining variants located in genes affecting cinitapride pharmacokinetics.

DISCUSSION

GORD and FD are highly prevalent in the world's population; consequently, the prescription of drugs for their treatment, including cinitapride, is very frequent and usually prolonged in time. ² To date, few studies have properly characterized cinitapride's pharmacokinetic profile. It is known as a substrate of CYP2C8 and CYP3A4, ⁷ but the clinical relevance of genetic polymorphisms in these genes on cinitapride's exposure remains unknown. Moreover, no pharmacogenetic guideline has been published to date reporting a clinically relevant phenotype of CYP2C8 that can be inferred based on allele genotyping. Table 6 shows a list of relevant CYP2C8 substrates which may be affected by the presence of gene polymorphisms. Further research should be conducted evaluating the impact of CYP2C8 polymorphisms on the effectiveness, safety, and pharmacokinetics of these drugs. Similarly, only recently a pharmacogenetic guideline on CYP3A4 has been published for the substrate quetiapine. ^{31 , 33 , 34} Hence, the present work is a convenient model to interrogate the effects of CYP3A4 and CYP2C8 variants or phenotypes on the enzyme's performance in a controlled environment.

The pharmacokinetic parameters here observed generally resembled those previously reported in the literature. For instance, in Chinese, Mexican and German populations, AUC_0–t and C_max after 1 mg cinitapride administration to young and healthy volunteers were 1580–3464pg*h/ml and 330–1398pg/ml, ^{8 , 11 , 12} while in the present study, an AUC_0–t of 3447±1261pg*h/ml and a C_max of 980±388pg*h/ml were observed, with significant differences between males and females. Nevertheless, a high pharmacokinetic interindividual variability is observed among studies. Although some of this variability can be explained due to the study design (e.g., depending on fasting or fed condition), a non‐negligible part of variability remains unexplained. When AUC_0–t and C_max were divided by the DW ratio to correct the impact of weight on pharmacokinetic variability, the abovementioned significant sex differences disappeared. It can therefore be concluded that sex does not influence cinitapride's exposure but weight does.

Concerning pharmacogenetics, CYP2C8 diplotypes had a clear effect on cinitapride exposure variability. CYP2C8*3 carriers showed a reduction in AUC of 42% and C_max of 35% compared to *1/*1 subjects. *4 allele carriers showed a 2.47‐fold increase in AUC and a 2.53‐fold increase in C_max compared to *3 allele carriers. Moreover, volunteers with the *1/*4 diplotype showed a 1.45‐fold and a 1.63‐fold increase in AUC/DW and C_max/DW compared to *1/*1 volunteers, but these association did not reach the level of significance due to the low sample size (i.e., only two *1/*4 individuals were identified). Accordingly, the following pharmacogenetic phenotypes can be proposed: CYP2C8 UMs (*3/*3), RMs (*1/*3), NMs (*1/*1), IMs (*1/*4), and PMs (*4/*4). To our knowledge, this is the first study to report a pharmacogenetic phenotype for CYP2C8. Since UMs and PMs were not sufficiently represented they could not be properly characterized. Additional studies are warranted to characterize UM and PM phenotypes. Not only are our findings relevant with respect to cinitapride, but also to numerous additional CYP2C8 substrates such as imatinib, loperamide, montelukast, ibuprofen, paclitaxel, pioglitazone, repaglinide, or rosiglitazone. Potentially, CYP2C8 phenotype may become a clinically relevant pharmacogenetic biomarker to individualize pharmacotherapy with various drugs.

Notwithstanding the current findings, the effect of CYP2C8 alleles should be described further in depth. CYP2C8 is involved in the metabolism of a diverse number of drugs, the prototypical CYP2C8 substrate being paclitaxel. ^{37 , 38} CYP2C8*2 and *3 alleles were associated with decreased metabolism of paclitaxel and arachidonic acid, ^{37 , 39} and CYP2C8*3 with increased metabolism of rosiglitazone, pioglitazone, and repaglinide. ^{40 , 41} These discrepancies encountered concerning the impact of CYP2C8*3 on the enzyme's activity may be explained in two ways. First, as a result of the linkage disequilibrium (LD) between CYP2C8*3 and CYP2C9*2. The variants encoding for these alleles (2130G>A (rs11572080) and 30411A>G (rs10509681) for CYP2C8*3 and 3608C>T (rs1799853) for CYP2C9*2) are located in a region of the CYP2C19, CYP2C8, and CYP2C9 locus in close proximity on chromosome 10, and are inherited together very frequently (i.e., 96% of CYP2C8*3 allele carriers also carry the CYP2C9*2 allele, and approximately 85% of CYP2C9*2 allele carriers also carry a CYP2C8*3 allele. ^{42 , 43} Here, we observed an apparent effect of CYP2C9 phenotype on cinitapride exposure variability; however, this association is not consistent as, even if cinitapride was metabolized via CYP2C9 (which to our knowledge has not been reported to date), IM and PMs should accumulate the drug in plasma compared to NMs, and the opposite effect was observed. Therefore, we confidently conclude that these effects are due to CYP2C8*3. Consistently, it should be emphasized that in the multivariate analysis, the association of CYP2C9 disappeared, supporting the above hypotheses. Second, the effect of CYP2C8*3 allele could be substrate‐specific. This effect is well described for other genes and drugs, such as CYP2D6*17, a well‐known decreased‐function allele, which is related to higher debrisoquine clearance. ^{44 , 45 , 46} Further studies should clarify the effect of CYP2C8*3 allele on cinitapride's or other substrates' pharmacokinetics, but we suggest that the LD with CYP2C9*2 is a clear confusing factor that may have led to biased conclusions in previous pharmacogenetic observational studies. In fact, the only subject with CYP2C9 *1/*3 and CYP2C8 *1/*1 diplotypes exhibited a normal value of AUC/DW and C_max/DW (data not shown), which confirms that CYP2C9 polymorphism does not impact the pharmacokinetics of cinitapride. In contrast, CYP2C8 *4 allele is generally assumed to cause a reduction in the enzyme's function for drugs such as montelukast ⁴⁷ and paclitaxel, ⁴⁸ which is consistent with the effects observed with cinitapride in the present study. Moreover, in a previous study conducted by our group, CYP2C8*3 allele was related to a higher clearance of ibuprofen as compared with individuals with CYP2C9 *1/*1and CYP2C8 *1/*1 diplotypes, ⁴⁹ which is consistent with the findings reported here.

One additional variant, ABCB1 C1236T, was related to cinitapride's exposure variability. ABCB1 gene variants determine the activity of the P‐glycoprotein, an efflux transporter localized in cell membranes throughout the entire body, which participates in the pharmacokinetics of several substrates. ^{50 , 51} The effect of C1236T variant on the transporter's performance is currently still unknown, ^{52 , 53} therefore further studies are warranted to confirm this association as no good comparators are available in the literature. ^{54 , 55 , 56} Concerning CYP3A4, we failed to demonstrate a significant effect of its phenotype on cinitapride exposure variability due to the low sample size, as only two *1/*22 (IMs) subjects were identified. ^{25 , 39}

Finally, cinitapride is marketed in a few countries and it is indicated for highly prevalent pathologies. Therefore, patients diagnosed with GORD or FD under treatment with cinitapride may be able to avoid a certain percentage of ADRs and even lack of efficacy. For instance, we speculate that CYP2C8 UMs could require a daily dose increase of 50%–100%, while PMs may require dose reductions to avoid ADRs. Alternatively, another drug may be used. However, the relevance of this work extends beyond the association with cinitapride, as other more relevant substrates could be affected by these phenotypes (e.g., chemotherapy agents like paclitaxel). Having characterized with such clarity the effect of CYP2C8 polymorphisms and identified the methodological problem of LD with CYP2C9 in the literature is a major finding. This opens the door to properly evaluate the impact of CYP2C8 phenotype on the exposure and safety of other relevant substrates of CYP2C8 such as ibuprofen, paclitaxel, and pioglitazone. Potentially, this will contribute to advancing precision pharmacotherapy with CYP2C8 substrates.

CONCLUSIONS

CYP2C8*3 and *4 alleles may be used to infer the PM, IM, NM, and UM phenotypes. Not only is this relevant with respect to cinitapride, but also with respect to numerous additional substrates such as imatinib, loperamide, montelukast, ibuprofen, paclitaxel, pioglitazone, repaglinide, or rosiglitazone. Further studies are needed to validate the utility of this phenotype with cinitapride (particularly the impact of UM and PM phenotypes) and other substrates.

AUTHOR CONTRIBUTIONS

D.M.C., P.Z., and F.A.‐S. wrote the manuscript. D.M.C., P.Z., and F.A.‐S. designed the research. D.M.C., P.Z., P.S.‐C., A.C., G.V.‐G., M.N.‐G., A.G.‐F., R.P.G., G.M.‐A., M.R., S.M.‐V., D.O., and F.A.‐S. performed the research. D.M.C., P.Z., and F.A.‐S. analyzed the data.

FUNDING INFORMATION

P.S.‐C. is financed by Universidad Autónoma de Madrid (FPI‐UAM, 2021). G.V.‐G. is co‐financed by Instituto de Salud Carlos III (ISCIII) and the European Social Fund (PFIS predoctoral grant, number FI20/00090). M.N.‐G. is financed by the ICI20/00131 grant, Acción Estratégica en Salud 2017–2020, ISCIII. P.Z. is financed by Universidad Autónoma de Madrid, Margarita Salas contract, grants for the requalification of the Spanish university system.

CONFLICT OF INTEREST

F.A.‐S. and D.O. have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Chemo, Cinfa, FAES, Farmalíder, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Italfarmaco Janssen‐Cilag, Kern, Normon, Novartis, Servier, Silverpharma, Teva, and Zambon. All the other authors declared no competing interests for this work.

Notes

Campodónico DM, Zubiaur P, Soria‐Chacartegui P, et al. CYP2C8 *3 and *4 define CYP2C8 phenotype: An approach with the substrate cinitapride. Clin Transl Sci. 2022;15:2613‐2624. 10.1111/cts.13386 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

Diana María Campodónico and Pablo Zubiaur contributed equally to this work.

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