Present situation of rational drug use in plateau area

Yanbin Chu; Rong Wang

doi:10.2478/fzm-2023-0012

Present situation of rational drug use in plateau area

doi: 10.2478/fzm-2023-0012

Yanbin Chu^{1, 2, 3},
Rong Wang^{1, 2, 3
, ,}

1.
Department of Pharmacy, the 940th Hospital of Joint Logistics Support force of Chinese People's Liberation Army, Lanzhou 730050, China
2.
Key Laboratory for Prevention and Remediation of Plateau Environmental Damage, Chinese People's Liberation Army, Lanzhou 730050, China
3.
Plateau Medical Laboratory for Chinese People's Liberation Army, Lanzhou 730050, China

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Corresponding author: Rong Wang, E-mail: wangrong-69@163.com

摘要

Abstract: Plateau is characterized by low oxygen, low pressure, strong radiation, cold and dryness, among which low oxygen is the main factor that affects the normal life activities of human body. Altitude hypoxia leads to significant changes in the metabolic characteristics of drugs in vivo, which in turn affects the efficacy and adverse actions of drugs. This paper summarizes the present situation of rational drug use in plateau area and pinpoints the existing problems. Meanwhile, we posit the strategies and measures for realizing rational and precise pharmacotherapy of plateau residents. First, we need to acquire a panoramic view of differential and relative pharmacokinetics and pharmacodynamics in between plateau area and plain area by carrying out comparative studies on drug metabolisms and on comprehensive drug efficacies and mechanisms. Second, we must apply the findings from basic research to clinical practice and formulate guidelines and recommendations of drug use for plateau habitants. Finally, we should eventually achieve precise and individualized drug use for plateau habitants based on their characteristic etiology and pathogenesis.
- plateau /
- hypoxia /
- rational drug use /
- pharmacokinetics

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Table 1. Comparison of pharmacokinetics parameters of furosemide in healthy volunteers in plain, fast-moving plateau and long-staying plateau^[9]

Parameters	Whole blood			Blood plasma
Parameters	Plain	Fast-moving plateau	Long-staying plateau	Plain	Fast-moving plateau	Long-staying plateau
K (h^-1)	0.76 ± 0.24	0.70 ± 0.20	0.61 ± 0.17	0.82 ± 0.26	0.71 ± 0.27	0.57 ± 0.16
t_1/2 (h)	0.97 ± 0.22	1.07 ± 0.29	1.24 ± 0.45	0.90 ± 0.20	1.13 ± 0.47	1.32 ± 0.52
V_d (L/kg)	10.44 ± 3.70	9.28 ± 1.87	10.50 ± 5.18	5.05 ± 1.89	4.60 ± 1.01	5.18 ± 2.27
CL (L/[h·kg])	0.39 ± 0.09	0.41 ± 0.08	0.42 ± 0.30	0.18 ± 0.04	0.20 ± 0.05	0.19 ± 0.11
AUC (μg/[h·mL])	5.22 ± 1.26	4.96 ± 0.99	5.56 ± 2.35	10.18 ± 2.39	9.23 ± 1.91	11.22 ± 4.52
C_max(μg/mL^-1)	2.29 ± 0.91	1.89 ± 0.72	1.89 ± 0.92	3.93 ± 1.39	3.54 ± 1.35	3.70 ± 1.82
t_max (h)	1.54 ± 0.66	1.38 ± 0.57	1.58 ± 0.79	1.58 ± 0.64	1.38 ± 0.57	1.58 ± 0.79
MRT (h)	9.47 ± 4.12	8.61 ± 4.16	12.97 ± 12.00	10.65 ± 4.44	9.62 ± 4.08	13.89 ± 10.37

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Table 2. Comparison of pharmacokinetics parameters of acetazolamide in healthy volunteers in plain, fast-moving plateau and long-staying plateau^[10]

Parameters	Whole blood			Blood plasma
Parameters	Plain	Fast-moving plateau	Long-staying plateau	Plain	Fast-moving plateau	Long-staying plateau
K (h^-1)	0.06 ± 0.02	0.07 ± 0.02	0.08 ± 0.06	0.12 ± 0.02	0.16 ± 0.03	0.13 ± 0.02
t_1/2 (h)	12.0 ± 3.0	10.2 ± 2.2	8.8 ± 5.9	6.0 ± 0.9	4.4 ± 0.8	5.3 ± 0.9
V_d (L/kg)	0.30 ± 0.12	0.24 ± 0.03	0.26 ± 0.08	0.39 ± 0.06	0.32 ± 0.08	0.44 ± 0.05
CL [L/(h·kg)]	0.29 ± 0.13	0.27 ± 0.07	0.31 ± 0.16	0.74 ± 0.09	0.82 ± 0.15	0.96 ± 0.18
AUC [μg/(h·mL)]	270.9 ± 107.0	264.2 ± 57.3	263.1 ± 147.3	94.1 ± 12.4	85.7 ± 10.2	70.9 ± 12.5
MRT (h)	19.6 ± 4.4	16.5 ± 3.2	18.5 ± 8.1	9.8 ± 1.1	7.7 ± 1.3	9.1 ± 1.4

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Table 3. Changes of Pharmacokinetic Parameters of Drugs under Hypoxia

Drugs	Species	MRT	C_max	t_1/2	K_e	AUC	V_d	CL	References
Ibuprofen	Rat	↑	—	↑	—	—	↑	↓	[14]
Diazepam	Rat	↑	↑	—	—	↑	—	—	[15]
Propranolol	Rat	↑	↑	↑	—	↑	↓	↓	[16]
Norfloxacin	Rat	↑	↓	↓	—	↓	↑	↑	[17]
Acetylsalicylic acid	Rabbit	↑	—	↑	↓	—	↓	↓	[18]
Gentamicin	Rabbit	↑	—	↑	↓	—	↑	↓	[18]
Phenobarbital	Rabbit	↑	—	↑	↓	—	↓	↓	[18]
Phenytoin	Rabbit	—	—	—	—	↑	—	↓	[19]
Theophylline	Rabbit	—	—	—	—	—	—	↓	[20]
Salbutamol	Rabbit	—	—	↑	—	—	↑	—	[21]
Diltiazem	Dog	—	—	—	—	—	↓	↓	[22]
Caffeine	Human	—	—	↓	↑	↓	—	↑	[23]
Indocyanine green	Human	—	—	—	—	↓	↑	↑	[23]
Acetazolamide	Human	↓	—	—	—	↓	↓	↑	[24]
Meperidine	Human	↑	—	↑	—	—	—	↓	[25]
Neurolithium	Human	↑	—	↑	—	—	↑	↓	[26]
Furosemide	Human	—	↓	—	—	↓	↓	↓	[27]
Prednisolone	Human	—	↑	—	—	↑	↓	↓	[28]
Sulfamethoxazole	Human	—	—	↑	—	↑	—	↓	[29]
Lidocaine	Human	↑	—	↑	—	—	↑	↓	[30]

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Table 4. Changes of expression and activity of drug metabolizing enzymes under hypoxia

Enzyme	Species	mRNA levels Protein expression		Activity	References
CYP1A1	Rabbit	↓	↓	↓	[31]
CYP1A2	Rat	↓	↓	↓	[32]
CYP2B4	Rabbit	↓	↓	↓	[33]
CYP2C5	Rabbit	↓	↓	↓	[33]
CYP2C9	Rat	↓	↓	↑	[32]
CYP2C16	Rabbit	↓	↓	↓	[33]
CYP2C19	Rat	↓	↓	↑	[32]
CYP2D6	Rat	↑	↑	↑	[32]
CYP2E1	Rat	↓	↓	↓	[34]
CYP3A1	Rat	↓	↓	↓	[34]
CYP3A4	Human	↓	↓	↓	[35]
CYP3A6	Rabbit	↑	↑	↑	[31]
NAT2	Rat	↓	↓	↓	[32]

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Table 5. Changes of expression and activity of drug transporters under hypoxia

Object	Drug transporter	mRNA levels	Protein expression	Activity	References
Liver	MDR1	↑	↑	↑	[36]
	MRP2	↑	↑	↑	[37]
	PEPT1	↑	↑	↑	[38]
	OATP1B1	↑	↑	↑	[38]
	OAT1	↑	↑	↑	[38]
	OCT1	↑	↑	↑	[38]
	OATP2	—	—	—	[39]
	BCRP	—	—	—	[39]
Intestine	MRP2	↑	↑	↑	[37]
	PEPT1	↑	↑	↑	[38]
	OATP1B1	↑	↑	↑	[38]
	OAT1	↑	↑	↑	[38]
	OCT1	↑	↑	↑	[38]
	MDR1	↓	↓	↓	[40]
Kidney	MDR1	↑	↑	↑	[37]
	PEPT1	↑	↑	↑	[37]
	OAT1	↑	↑	↑	[38]
	OCT1	↑	↑	↑	[38]
	MRP2	↓	↓	↓	[37]
	OATP1B1	—	—	—	[38]
Heart	MDR1	↓	↓	↓	[36]

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