Mechanisms and the clinical relevance of complex drug–drug interactions

Figures & data

Figure 1 Drug-metabolizing enzymes and drug transporters in (A) an enterocyte, (B) a brain endothelial cell, (C) a placental trophoblast, (D) hepatocyte and biliary endothelial cells, and (E) a renal proximal tubule cell.

Notes: The drug metabolizing enzymes are shown as blue circles and the transporters are shown as arrows. The direction of the arrow reflects the direction of transport.
Abbreviations: BCRP, breast cancer resistance protein; CYP1A2, CYP/CYP450 1A2; CYP3A4, CYP/CYP450 3A4; MCT1, monocarboxylate transporter 1; OAT1, organic anionic transporter 1; OAT3, organic anionic transporter 3; OATP1A2, organic anionic transporting polypeptide 1A2; OCTs, organic cationic transporters; MRP4, multidrug resistance protein 4; Pgp, P-glycoprotein.

Table 1 Pharmacokinetically mediated DDIs

ADME	Protein	“Victim” drug	“Perpetrator” drug	DDI	PK effect	Ref
Intestinal absorption	Pgp	Talinolol	Erythromycin	Inhibition	AUC: increased Cmax: increased F: increased	^Citation20
Intestinal absorption	Pgp	Talinolol	Rifampicin	Induction	AUC: decreased 35% Cmax: decreased 38% F: decreased 35%	^Citation21
Intestinal absorption	BCRP	Rosuvastatin	Fostamatinib	Inhibition	AUC: increased 196% Cmax: increased 188% F: increased	^Citation22,Citation23
Intestinal absorption	OATP1A2	Fexofenadine	Naringin	Inhibition	AUC: decreased 22% Cmax: decreased 18% F: decreased	^Citation24
Intestinal absorption	CYP3A4	Midazolam	Itraconazole	Inhibition	AUC: increased Fg: increased	^Citation33
Intestinal absorption	CYP3A4	Alfentanil	Troleandomycin	Inhibition	AUC: increased Cmax: increased Fg: increased	^Citation34
Intestinal absorption	CYP3A4	Alfentanil	Rifampicin	Induction	AUC: decreased Cmax: decreased Fg: decreased	^Citation34
BBB distribution	Pgp	Verapamil	Tariquidar	Inhibition	VT,brain: increased	^Citation53
Placental distribution	Pgp	Verapamil	Cyclosporine A	Inhibition	VT,fetus: increased	^Citation64
Liver metabolism	CYP3A4	Felodipine	Intraconazole	Inhibition	AUC: increased 634% Cmax: increased 775% F: increased ~400% t1/2: increased 171%	^Citation79,Citation80
Liver metabolism	CYP3A4	Nifedipine	Rifampicin	Induction	AUC: decreased 30% F: decreased ~800% t1/2: decreased 26%	^Citation81
Liver metabolism	CYP1A2	Caffeine	Fluvoxamine	Inhibition	AUC: increased 27% Cmax: increased 26% t1/2: increased >11-fold	^Citation83
Liver metabolism	UGT2B7	AZT	Valproate	Inhibition	AUC: increased 44% Cmax: increased 29%	^Citation91
Liver metabolism	UGT2B7	AZT	Rifampicin	Induction	AUC: decreased 47% Cmax: decreased 43% F: decreased	^Citation93,Citation94
Renal excretion	Pgp	Digoxin	Various	Inhibition	AUC: increased Cmax: increased	^Citation97
Renal excretion	OAT1, OAT3	Furosemide	Probenecid	Inhibition	AUC: increased 2.7-fold CLR: decreased 66%	^Citation96,Citation101
Renal excretion	OCTs	Metformin	Lansoprazole	Inhibition	AUC: increased Cmax: increased CLR: decreased t1/2: increased	^Citation102
Biliary excretiona	Pgp	Thienorphine	Tarquidar	Inhibition	AUC: increased ~3-fold Cmax: increased ~3-fold t1/2: decreased 56%	^Citation106

Notes:

a Data from Kong et al.¹⁰⁶ The t_1/2 of thienorphine is “paradoxically” increased due to interrupted enterohepatic circulation.

Abbreviations: AUC, area under the curve; C_max, maximum drug plasma concentration; CL_R, renal clearance; DDI, drug–drug interactions; F, oral bioavailability; F_g, gut oral bioavailability; PK, pharmacokinetic; Ref, reference; t_1/2, elimination half time; VT,brain, apparent brain volume distribution; V_T,fetus, apparent fetal volume distribution.

Table 2 Pharmacodynamically mediated DDIs

PD DDI	Drug #1	Drug #2	PD effects	Ref.
Additive	Liraglutide	Insulin determir	EDEC50s: unchanged Emaxs of drugs additive PD: glucose lowered	^Citation118
Additive	Phenprocoumon	NSAIDS	EDEC50s: unchanged Emaxs of drugs additive PD: additive anticoagulant effect	^Citation120
Synergistic	Diphenhydramine	Ethanol	Emax of combination greater than sum of individual Emaxs PD: enhanced impairment	^Citation122
Synergistic	Tramadol	Acetaminophen	EDEC50s: reduced Emax of combination greater than sum of individual Emaxs PD: enhanced pain reduction	^Citation125
Competitive antagonistic	Naloxone	Opioids	EDEC50s: increased Emaxs: unchanged PD: dampening of opioid effects	^Citation129
Noncompetitive allosteric antagonistic	Ruthenium red	Capsaicin	EDEC50s : unchanged Emaxs: Emax of capsaicin reduced PD: reduce irritant effect of capsaicin.	^Citation127

Abbreviations: DDI, drug -drug interactions; NSAIDs, nonsteroidal anti-inflammatory drugs; PD, pharmacodynamics; Ref, reference.

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